Stimulants pp 335-387 | Cite as

Drug Metabolism: Review of Principles and the Fate of One-Ring Psychotomimetics

  • Neal CastagnoliJr.
Part of the Handbook of Psychopharmacology book series (HBKPS, volume 11)


Interest in the metabolic fate of compounds foreign to the body (xenobiotics) has intensified dramatically during the past decade. Research efforts are derived today from a variety of disciplines and any attempt to review the entire field is likely to require a “team of experts.” Fortunately, a number of books that cover various aspects of drug metabolism have appeared recently. The most chemically oriented is the Testa and Jenner monograph (1976), which provides an excellent description of biotransformation processes with much fine molecular detail. The Chemical Society, London, publishes a good review series entitled “Foreign Compound Metabolism in Mammals” (Hathway, 1975). A bibliographic survey, “The Fate of Drugs in the Organism” (Hirtz, 1976), has recorded 9000 references (through about 1972) dealing with various aspects of drug metabolism. Two textbook-type publications (Goldstein et al., 1974; La Du et al., 1971) are mainly concerned with the fate and mechanism of action of small molecules. The more traditional textbooks in medicinal chemistry contain good chapters on drug metabolism (McMahon, 1970; Daniels and Jorgensen, 1977). Biologically oriented material will be found in the series “Concepts in Biochemical Pharmacology,” particularly Part 2 (Brodie and Gillette, 1971) and Part 3 (Gillette and Mitchell, 1975). The publications of the proceedings of a number of symposia provide first-rate discussions of specific topics. Two symposium publications focus on in vitro aspects of microsomal oxidations (Estabrook et al., 1973a; Gillette et al., 1969).


Drug Metabolism Liver Microsome Metabolic Fate Rabbit Liver Biochemical Pharmacology 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aboul-Enein, H. Y., Schauberger, C. W., Hansen, A. R., and Fischer, L. J., 1975, Synthesis of an active hydroxylated glutethimide metabolite and some related analogs with sedative-hypnotic and anticonvulsant properties, J. Med. Chem. 18:736–741.PubMedGoogle Scholar
  2. Aldous, F. A. B., Barrass, B. C., Brewster, K., Buxton, D. A., Green, D. M., Pinder, R. M., Rich, P., Skeels, M., and Tutt, K. J., 1974, Structure-activity relationships in psychotomimetic phenylalkylamines, J. Med. Chem. 17:1100–1111.PubMedGoogle Scholar
  3. Alexanderov, K., Brooks, P., King, H. W. S., Osborne, M. R., and Thompson, M. H., 1976, Comparison of the metabolism of benzo(a)-pyrene and binding to DNA caused by rat liver nucleii and microsomes, Chem. Biol. Interaction 12:269–277.Google Scholar
  4. Alles, G. A., 1933, The comparative physiological actions of dl-β-phenylisopropylamines. I. Pressor effect and toxicity, J. Pharmacol. Exp. Therap. 47:339–354.Google Scholar
  5. Alles, G. A., 1939, Comparative actions of optically isomeric phenisopropylamines, Am. J. Physiol. 126:420.Google Scholar
  6. Alleva, J. J., 1963, Metabolism of tranylcypromine-C14 and dl-amphetamine-C14 in the rat. J. Med. Chem. 6:621–624.PubMedGoogle Scholar
  7. Andreoli, V. M., Danieli, B., and Tonon, G. C., 1973, Significance of methoxylated derivatives in amphetamine psychosis, Riv. Farmacol. Ter. 4:1a–21a.Google Scholar
  8. Angrist, B., and Gershon, S., 1971, A pilot study of pathogenic mechanisms in amphetamine psychosis utilizing differential effects of d and l amphetamines, Pharmakopsych. Neuro-Psychopharmakol. 4:64–75.Google Scholar
  9. Angrist, B. M., Schweitza, J. W., Friedhoff, A. J., and Gershon, S., 1970, Investigation of p-methoxyamphetamine excretion in amphetamine induced psychosis, Nature 225:651–652.PubMedGoogle Scholar
  10. Angrist, B. M., Shopsin, B., and Gershon, S., 1971, Comparative psychotomimetic effects of stereoisomers of amphetamine, Nature 234:152–153.PubMedGoogle Scholar
  11. Axelrod, J., 1955, The enzymatic deamination of amphetamine (Benzedrine), J. Biol. Chem. 214:753–763.PubMedGoogle Scholar
  12. Axelrod, J., 1964, Enzymatic oxidation of epinephrine to adrenochrome by the salivary gland, Biochim. Biophys. Acta 85:247–254.PubMedGoogle Scholar
  13. Axelrod, J., 1971, Methyltransferase enzymes in the metabolism of physiologically active compounds and drugs in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 609–619, Springer-Verlag, Berlin.Google Scholar
  14. Bachur, N. R., 1976, Cytoplasmic aldo-keto reductases: a class of drug metabolizing enzymes, Science 193:595–597.PubMedGoogle Scholar
  15. Bartsch, H., Miller, J. A., and Miller, E. C., 1972, Activation of carcinogenic aromatic hydroxylamines by enzymatic O-acetylation, Proc. Am. Assoc. Cancer Res. 13:12.Google Scholar
  16. Beckett, A. H., 1974, Separation and detection of unstable metabolites of amphetamines, analgetics, and phenothiazines in The Poisoned Patient: The Role of the Laboratory, Ciba Foundation Symposium 2b (new series), pp. 57–82, Elsevier, Amsterdam.Google Scholar
  17. Beckett, A. H., 1976, Metabolic N-oxidation of secondary and primary aromatic amines as a route to ring hydroxylation to various N-oxygenated products, and to dealkylation of secondary amines. Biochem. Pharmacol. 25:211–214.PubMedGoogle Scholar
  18. Beckett, A. H., and Al-Sarraj, S., 1972, The mechanism of amphetamine enantiomorphs by liver microsomal preparations from different species. J. Pharm. Pharmacol. 24:174–176.PubMedGoogle Scholar
  19. Beckett, A. H., and Al-Sarraj, S., 1973, The identification, properties and analysis of N-hydroxyamphetamine—a metabolite of amphetamine, J. Pharm. Pharmacol. 25:328–334.Google Scholar
  20. Beckett, A. H., and Bélanger, P. M., 1974a, Identification of three metabolic products of phentermine after liver microsomal incubation, Xenobiotica 5:509–519.Google Scholar
  21. Beckett, A. H., and Bélanger, P. M., 1974b, The mechanism of metabolic N-oxidation of phentermine and chlorphentermine to their hydroxylamino-and nitroso-compounds, J. Pharm. Pharmacol. 26:558–560.Google Scholar
  22. Beckett, A. H., and Bélanger, P. M., 1974c, Metabolism of chlorphentermine and phentermine in man to yield hydroxylamine, C-nitroso-and nitro-compounds, J. Pharm. Pharmacol. 26:205–206.PubMedGoogle Scholar
  23. Beckett, A. H., and Bélanger, P. M., 1975a, Metabolic incorporation of oxygen into primary and secondary aliphatic amines and the consequences in carbon-nitrogen bond cleavage, J. Pharm. Pharmacol. 27:547–552.PubMedGoogle Scholar
  24. Beckett, A. H., and Bélanger, P. M., 1975b, The identification and analysis of the metabolic products of mephentermine, J. Pharm. Pharmacol. 27:928–936.PubMedGoogle Scholar
  25. Beckett, A. H., and Bélanger, P. M., 1976, Metabolic N-oxidation of secondary and primary aromatic amines as a route ring hydroxylation, to various N-oxygenated products, and to dealkylation of secondary amines, Biochem. Pharmacol. 25:211–214.PubMedGoogle Scholar
  26. Beckett, A. H., and Gibson, G. C., 1975, Microsomal N-hydroxylation of dibenzylamine, Xenobiotica 5:677–686.PubMedGoogle Scholar
  27. Beckett, A. H., and Midha, K. K., 1974, The identification of four metabolic products after incubation of p-methoxy-amphetamine with liver preparations of various species, Xenobiotica 4:297–312.PubMedGoogle Scholar
  28. Beckett, A. H., and Morton, D. M., 1966, The metabolism of isomeric methoxyoxindoles, Biochem. Pharmacol. 15:1847–1855.Google Scholar
  29. Beckett, A. H., and Rowland, M., 1964, A specific method for the determination of amphetamine in urine, J. Pharm. Pharmacol. 16:27T–31T.Google Scholar
  30. Beckett, A. H., and Rowland, M., 1965a, Determination and indentification of amphetamine in urine, J. Pharm. Pharmacol. 17:59–60.PubMedGoogle Scholar
  31. Beckett, A. H., and Rowland, M., 1965b, Urinary excretion kinetics of amphetamine in man, J. Pharm. Pharmacol. 17:628–639.PubMedGoogle Scholar
  32. Beckett, A. H., and Shenoy, E. V. B., 1973, The effect of N-alkyl chain length and stereochemistry on the absorption, metabolism, and urinary excretion of N-alkylamphetamines in man, J. Pharm. Pharmacol. 25:793–799.PubMedGoogle Scholar
  33. Beckett, A. H., and Tucker, G. T., 1966, A method for evaluation of some oral prolonged release forms of dexamphetamine in man, using urinary excretion data, J. Pharm. Pharmacol. 18:725–755.Google Scholar
  34. Beckett, A. H., Salmon, J. A., and Mitchard, M., 1969, The relation between blood levels and urinary excretion of amphetamine under controlled acidic and under fluctuating urinary pH values using (14C) amphetamine, J. Pharm. Pharmacol. 21:251–258.PubMedGoogle Scholar
  35. Beckett, A. H., Coutts, R. T., and Ogunbona, F. A., 1973a, Metabolism of amphetamines, identification of N-oxygenated products by gas chromatography and mass spectometers, J. Pharm. Pharmacol. 25:708–717.PubMedGoogle Scholar
  36. Beckett, A. H., Coutts, R. T., and Ogunbona, F. A., 1973b, N-ethyl-α-methyl-α-(m-trifluromethylbenzyl)nitrone—the major in vitro metabolic product of fenfluramine in guinea pig liver microsomal fractions, J. Pharm. Pharmacol. 25:190–192.PubMedGoogle Scholar
  37. Beckett, A. H., Coutts, R. T., and Ogunbona, F. A., 1974a, The structure of nitrones derived from amphetamine, J. Pharm. Pharmacol. 26:312–316.PubMedGoogle Scholar
  38. Beckett, A. H., Jones, G. R., and Al-Sarraj, S., 1974b, Metabolic N-and α-C-oxidation of norephedrine by rabbit liver microsomal fractions and synthesis of the metabolic products, J. Pharm. Pharmacol. 26:945–951.PubMedGoogle Scholar
  39. Beland, F. A., and Harvey, R. G., 1976, Reactions of the K-region oxides of carcinogenic and related polycyclic hydrocarbons with nucleophiles: stereochemistry and regioselectivity, J. Am. Chem. Soc. 98:4963–4970.PubMedGoogle Scholar
  40. Belvedere, G., Rovei, V., Pantarotto, C., and Frigerio, A., 1975, Identification of cyclobenzaprine-10,11-epoxide and other metabolites after incubation of cyclobenzaprine with rat liver microsomes, Xenobiotica 5:765–772.Google Scholar
  41. Benington, F., Morin, R. D., Beaton, J., Smythies, J. R., and Bradley, R. J., 1973, Comparative effects of stereoisomers of hallucinogenic amphetamines, Nature New Biol. 242:185–186.PubMedGoogle Scholar
  42. Bernheim, F., and Bernheim, M. L. C., 1938, The oxidation of mescaline and certain other amines. J. Biol. Chem. 123:317–326.Google Scholar
  43. Bickel, M. H., 1969, The pharmacology and biochemistry of N-oxides, Pharmacol. Rev. 21:325–355.PubMedGoogle Scholar
  44. Bickel, M. H., and Gigon, P. L., 1971, Metabolic interconversions and binding of imipramine, imipramine-N-oxide, and desmethylimipramine in rat liver slices, Xenobiotica 1:631–641.PubMedGoogle Scholar
  45. Blank, C. L., Kissinger, P. T., and Adams, R. N., 1972, 5,6-Dihydroxyindole formation from oxidized 6-hydroxydopamine, Eur. J. Pharmacol. 19:391–394.PubMedGoogle Scholar
  46. Blaschko, H., 1972, Introduction. Catecholamines 1922–1971, in Catecholamines (Blaschko, H., and Muscholl, E., eds.), p. 8, Springer-Verlag, Berlin.Google Scholar
  47. Blaschko, H., Ferro-Luzzi, G., and Hawes, R., 1958, Enzymic oxidation of mescaline by mammalian plasma, Biochem. Pharmacol. 1:101.Google Scholar
  48. Bleecker W., Capdevila, J., and Agosin, M., 1973, Sequential solubilization of microsomal mixed function oxidases, J. Biol. Chem. 248:8474–8481.PubMedGoogle Scholar
  49. Block, W., 1953, In vitro-Versuche zum Einbau von 14C-Mescalin and 14C-β Phenylethylamin in Protein, III Mitteilung, Hoppe-Seyler’s Z. Phys. Chem. 294:49–56.Google Scholar
  50. Block, W., 1958, The mescaline psychosis in Chemical Concepts of Psychosis (Rinkel, M., and Denber, H. C., eds.), pp. 106–119, McDowell, Oblensky, New York.Google Scholar
  51. Bobik, A., Holder, G. M., Ryan, A. J., and Wiebe, L. I., 1975, Inhibitors of hepatic mixed function oxidases. 1. The metabolism of 2,6-dihydroxy-2-hydroxy-6-methoxy-and 2,6-dimethoxyacetophenones, Xenobiotica 5:65–72.PubMedGoogle Scholar
  52. Boyd, D. R., Daly, J. W., and Jerina, D. M., 1972, Rearrangement of (1-2H)-and (2-2H) naphthalene 1,2-oxides to 1-naphthol mechanism of the NIH shift, Biochemistry 11:1961–1966.PubMedGoogle Scholar
  53. Boyland, E., 1962, Mercapturic acid conjugation in Proc. First Int. Pharmacol. Meeting 6 (Brodie, B. B., and Erdos, E. G., eds.), pp. 65–76, Pergamon, Oxford.Google Scholar
  54. Boyland, E., 1971, Mercapturic acid conjugation, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 584–608, Springer-Verlag, Berlin.Google Scholar
  55. Bridges, J. W., Gorrod, J. W., and Parke, D. V. (eds.), 1972, Biological Oxidation of Nitrogen in Organic Molecules, Wiley, New York.Google Scholar
  56. Brodie, B. B., and Gillette, J. R. (eds.), 1971, Concepts in Biochemical Pharmacology, Part 2, Springer-Verlag, Berlin.Google Scholar
  57. Brodie, B. B., Axelrod, J., Shore, P. A., and Udenfriend, S., 1954, Ascorbic acid in aromatic hydroxylation. II. Products formed by reaction of substrates with ascorbic acid, ferrous ion, and oxygen, J. Biol. Chem. 208:741–750.PubMedGoogle Scholar
  58. Brodie, B. B., Axelrod, J., Cooper, J. R., Gaudette, L., La Du, B. N., Mitoma, C, and Udenfriend, S., 1955, Detoxification of drugs and other foreign compounds by liver microsomes, Science 121:603–604.PubMedGoogle Scholar
  59. Brodie, B. B., Gillette, J. R., and La Du, B. N., 1958, Enzymatic metabolism of drugs and other foreign compounds, Ann. Rev. Biochem. 27:427–454.PubMedGoogle Scholar
  60. Brodie, B. B., Cho, A. K., and Gessa, G. L., 1970, Possible role of p-hydroxynorephedrine in the depletion of norepinephrine induced by α-amphetamine and in tolerance to this drug, in Amphetamines and Related Compounds (Costa, E., and Garattini, S., eds.), pp. 217–230, Raven Press, New York.Google Scholar
  61. Browne, R. G., and Ho, B. T., 1975, Discriminative stimulus properties of mescaline: mescaline or metabolite? Pharmacol. Biochem. Behav. 3:109–114.PubMedGoogle Scholar
  62. Bush, M. T., and Weller, W. L., 1972, Metabolic fate of hexobarbital (HB), Drug. Metab. Rev. 1:249–290.Google Scholar
  63. Butcher, L. L., 1975, Degenerative processes after punctate intracerebral administration of 6-hydroxydopamine, Neural Transmission 37:189–208.Google Scholar
  64. Calder, I. C., Creek, M. J., and Williams, P. J., 1973, N-hydroxylation of p-acetophenetidide as a factor in neprotoxicity, J. Med. Chem. 16:499–502.PubMedGoogle Scholar
  65. Caldwell, J., Dring, L. G., and Williams, R. T., 1972a, Metabolism of (14C) methamphetamine in man, the guinea pig and the rat, Biochem. J. 129:11–22.PubMedGoogle Scholar
  66. Caldwell, J., Dring, L. G., and Williams, R. T., 1972b, Norephedrines as metabolites of (14C) amphetamine in urine of man, Biochem. J. 129:23–24.PubMedGoogle Scholar
  67. Caldwell, J., Köster, U., Smith, R. L., and Williams, R. T., 1975, Species variations in the N-oxidation of chlorphetamine, Biochem. Pharmacol. 24:2225–2232.PubMedGoogle Scholar
  68. Carlsson, A., and Lindquist, M., 1962, In vivo decarboxylation of α-methyl DOPA and α-methyl metatyrosine, Acta Physiol. Scand. 54:87–94.PubMedGoogle Scholar
  69. Chang, C. K., and Dolphin, D., 1976, Oxygen binding to mercaptide-heme complexes. Models for reduced cytochrome P-450, J. Am. Chem. Soc. 98:1607–1609.PubMedGoogle Scholar
  70. Charlampous, K. D., Orengo, A., Walker, K. E., and Kinross-Wright, J., 1964, Metabolic fate of β-(3,4,5-trimethoxyphenyl) in humans: isolation and identification of 3,4,5-trimethoxyphenyl acetic acid, J. Pharmacol. Exp. Therap. 145:242–246.Google Scholar
  71. Charalampous, K. D., Walker, K. E., and Kinross-Wright, J., 1966, Metabolic fate of mescaline in man, Psychopharmacologia 9:48–63.PubMedGoogle Scholar
  72. Cho, A. K., Lindeke, B., and Hodshon, B. J., 1972, The N-hydroxylation of phentermine (2-methyl-1-phenylisopropylamine) by rabbit liver microsomes, Res. Commun. Chem. Pathol. Pharmacol. 4:519–527.PubMedGoogle Scholar
  73. Cho, A. K., Schaeffer, J. C., and Fischer, J. F., 1975a, Accumulation of 4-hydroxyamphetamine by rat stiatal homogenates, Biochem. Pharmacol. 24:1540–1542.PubMedGoogle Scholar
  74. Cho, A. K., Hodshon, B. J., Lindeke, B., and Jonnson, J., 1975b, The p-hydroxylation of amphetamine and phentermine by rat liver microsomes, Xenobiotica 5:531–538.PubMedGoogle Scholar
  75. Claude, A., 1969, Microsomes, endoplasmic reticulums, and interactions of cytoplasmic membranes, in Microsomes and Drug Oxidations (Gillette, J. R., Estabrook, R. W., Fouts, J. R., and Mannering, G. J., eds.), pp. 3–39, Academic Press, New York.Google Scholar
  76. Cohen, G., and Collins, M., 1970, Alkaloids from catecholamines in adrenal tissue: possible role in alcoholism, Science 167:1749–1751.PubMedGoogle Scholar
  77. Colvin, M., Padgett, C. A., and Fenselau, C., 1973, A biologically active metabolite of cyclophosphamide, Cancer Res. 33:915–918.PubMedGoogle Scholar
  78. Comai, K., and Gaylor, J. L., 1973, Existence and separation of three forms of cytochrome P-450 from rat liver microsomes, J. Biol. Chem. 248:4947–4955.PubMedGoogle Scholar
  79. Connell, P. H., 1958, Amphetamine Psychosis, Chapman and Hall, London.Google Scholar
  80. Consolo, S., Dolfini, E., Garattini, S., and Valzelli, L., 1967, Desipramine and amphetamine metabolism, J. Pharm. Pharmacol. 19:253–256.PubMedGoogle Scholar
  81. Coon, M. J., Strobe, H. W., and Boyer, R. F., 1973, On the mechanism of hydroxylation reactions catalyzed by cytochrome P-450, Drug. Metab. Disp. 1:92–97.Google Scholar
  82. Cooper, D. Y., Schleyer, H., and Rosenthal, O., 1973, Chemistry of cytochrome P-450 purified from endocrine systems, Drug. Metab. Disp. 1:21–28.Google Scholar
  83. Cooper, J. R., Axelrod, J., and Brodie, B. B., 1954, Inhibitory effects of β-diethylaminoethyl diphenyl-propylacetate on a variety of drug metabolic pathways in vitro, J. Pharmacol. Exp. Therap. 112:55–63.Google Scholar
  84. Costa, E., and Groppetti, 1970, Biosynthesis and storage of catecholamines in tissues of rats injected with various doses of d-amphetamine in Amphetamines and Related Compounds (Costa, E., and Garattini, S., eds.), pp. 231–255, Raven Press, New York.Google Scholar
  85. Coutts, R. T., Dawe, R., Dawson, G. W., and Kovach, S. H., 1976a, In vitro metabolism of 1-phenyl-2-propanone oxime in rat liver homogenates, Drug. Metab. Disp. 4:35–39.Google Scholar
  86. Coutts, R. T., Dawson, G. W., and Beckett, A. H., 1976b, In vitro metabolism of 1-phenyl-2-(n-propylamino)propane (N-propylamphetamine) by rat liver homogenates, J. Pharm. Pharmacol. 28:815–821.PubMedGoogle Scholar
  87. Creaven, P. J., Barbee, T., and Roach, M. K., 1970, The interaction of ethanol and amphetamine metabolism, J. Pharm. Pharmacol. 22:828–831.PubMedGoogle Scholar
  88. Dagne, E., and Castagnoli, N., Jr., 1972, Structure of hydroxycotinine, a nicotine metabolite, J. Med. Chem. 15:356–360.PubMedGoogle Scholar
  89. Dajani, R. M., Gorrod, J. W., and Beckett, A. H., 1975, In vitro hepatic and extrahepatic reduction of (-)-nicotine-1′-N-oxide in rats, Biochem. Pharmacol. 24:109–117.PubMedGoogle Scholar
  90. Daly, J., Axelrod, J., and Witkop, B., 1962, Methylation and demethylation in relation to the in vitro metabolism of mescaline, Ann. N.Y. Acad. Sci. 96:37–43.PubMedGoogle Scholar
  91. Daly, J., Guroff, G., Udenfriend, S., and Witkop, B., 1967, Hydroxylation induced migrations of tritium of several substrates of liver aryl hydroxylases, Arch. Biochem. Biophys. 122:218–223.PubMedGoogle Scholar
  92. Daly, J. W., Jerina, D. M., and Witkop, B., 1972, Arene oxides and the NIH shift: the metabolism toxicity and carcinogenicity of aromatic compounds, Experientia 28:1129–1149.PubMedGoogle Scholar
  93. Daniels, T. C., and Jorgensen, E. C., 1977, Metabolic changes of drugs and related organic compounds, in Textbook of Organic, Medicinal, and Pharmaceutical Chemistry, 7th ed. (Wilson, C. O., Gisvold, O., and Dorerge, R. F., eds.), pp. 63–119, Lippincott, Philadelphia.Google Scholar
  94. Davis, J. M., and Janowsky, D. S., 1973, Amphetamine and methylphenidate psychosis in Frontiers in Catecholamine Research (Usdin, E., and Snyder, S., eds.), pp. 977–981, Pergamon Press, New York.Google Scholar
  95. Davis, M., Harrison, N. G., Ideo, G., Portmann, B., Labadarios, D., and Williams, R., 1976, Paracetamol metabolism in the rat: relationship to covalent binding and hepatic damage, Xenobiotica 6:249–256.PubMedGoogle Scholar
  96. Davis, V. E., and Walsh, M. J., 1970, Alcohol, amines and alkaloids, a possible biochemical basis for alcohol addiction, Science 167:1005–1007.PubMedGoogle Scholar
  97. Debackere, M., and Massart-Lëen, A. M., 1965, Identification and metabolism of amphetamine in some domestic animals, Arch. Int. Pharmacodyn. 155:459–462.Google Scholar
  98. De Matteis, F., 1973, Drug-induced destruction of cytochrome P-450, Drug Metab. Disp. 1:267–274.Google Scholar
  99. Demisch, L., and Seilar, N., 1975, Oxidative metabolism of mescaline in the central nervous system. V. In vitro deamination of mescaline to 3,4,5-trimethoxybenzoic acid, Biochem. Pharmacol. 24:575–580.PubMedGoogle Scholar
  100. Dingell, J. V., and Bass, A. D., 1969, Inhibition of the hepatic metabolism of amphetamine by desipramine, Biochem. Pharmacol. 18:1535–1538.PubMedGoogle Scholar
  101. Dring, L. G., and Caldwell, J., 1973, Metabolism of the amphetamines in man and laboratory animals, in Psychopharmacol. Sex. Disord. Drug Abuse, Proc. Symp. Congr. Coll. Int. Neuro-Psychopharmacol, 8th ed. (Ban, T. A., ed.), pp. 577–583, North-Holland, Amsterdam.Google Scholar
  102. Dring, L. G., Smith, R. L., and Williams, R. T., 1966, The fate of amphetamine in man and other animals, J. Pharm. Pharmacol. 18:402–404.PubMedGoogle Scholar
  103. Dring, L. G., Smith, R. L., and Williams, R. T., 1968, A precursor of benzyl methyl ketone in amphetamine urine, Biochem. J. 109:10.Google Scholar
  104. Dring, L. G., Smith, R. L., and Williams, R. T., 1970, The metabolic fate of amphetamine in man and other species, Biochem. J. 116:425–435.PubMedGoogle Scholar
  105. Dutton, G. J., 1971, Glucuronide-forming enzymes, in Concepts in Biochemical Pharmacology Part 2, (Brodie, B. B., and Gillette, J. R., eds.), pp. 378–400, Springer-Verlag, Berlin.Google Scholar
  106. Ellinwood, E. H., Jr., 1971, Assault and homicide associated with amphetamine abuse, Am. J. Psychiatry 127:1170–1175.PubMedGoogle Scholar
  107. Ellison, T., Gutzait, L., and van Zoon, E. J., 1966, The comparative metabolism of d-amphetamine-14C in the rat, dog and monkey, J. Pharmacol. Exp. Therap. 152:383–387.Google Scholar
  108. El Masry, A. M., Smith, J. N., and Williams, R. T., 1956, Studies in detoxification. 69. The metabolism of alkylbenzenes: n-propylbenzene and n-butylbenzene with further observations on ethylbenzene. Biochem. J. 64:50–56.PubMedGoogle Scholar
  109. Estabrook, R. W., Gillette, J. R., and Leibman, K. C. (eds.), 1973a, Microsomes and Drug Oxidations, Williams and Wilkins, Baltimore, Maryland.Google Scholar
  110. Estabrook, R. W., Gillette, J. R., and Leibman, K. C. (eds.), 1973b, Microsomes and Drug Oxidations, Chapter 8, Extrahepatic drug metabolism, pp. 342–379, Williams and Wilkins Co., Baltimore, Maryland.Google Scholar
  111. Estabrook, R. W., Matsubara, T., Mason, J. I., Werringloer, J., and Baron, J., 1973c, Studies on the molecular function of cytochrome P-450 during drug metabolism, Drug Metab. Disp. 1:98–110.Google Scholar
  112. Estabrook, R. W., Gillette, J. R., and Leibman, K. C. (eds.), 1973d, Microsomes and Drug Oxidations, Chapter 5, Inducers of drug metabolism, pp. 199–325, Williams and Wilkins, Baltimore, Maryland.Google Scholar
  113. Estabrook, R. W., Gillette, J. R., and Leibman, K. C., (eds.), 1973e, Microsomes and Drug Oxidations, Chapter 4, Effects of inhibitors on drug metabolism, pp. 162–198, Williams and Wilkins, Baltimore, Maryland.Google Scholar
  114. Eyer, P., Kiese, M., Lipowsky, G., and Weger, N., 1974, Reactions of 4-dimethylaminophenol with hemoglobin, and autoxidation of 4-dimethylaminophenol, Chem.-Biol. Interactions 8:41–59.Google Scholar
  115. Faulkner, J. K., and Smith, K. J. A., 1972, Dealkylation and N-oxidation in the metabolism of 1-diethylcarbamyl-4-methylpiperazine in the rat, Xenobiotica 2:59–68.PubMedGoogle Scholar
  116. Foster, A. B., Jarman, M., Stevens, J. D., Thomas, P., and Westwood, J. H., 1974, Isotope effects in O-and N-demethylations mediated by rat liver microsomes: an application of direct insertion electron impact mass spectrometry, Chem.-Biol. Interactions 9:327–340.Google Scholar
  117. Fouts, J. R., 1971, Some morphological characteristics of hepatocyte endoplasmic reticulum and some relationships between endoplasmic reticulum, microsomes, and drug metabolism, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 243–250, Springer-Verlag, Berlin.Google Scholar
  118. Fouts, J. R., and Brodie, B. B., 1955, Inhibition of drug metabolic pathways by the potentiating agent, 2,4-dichloro-6-phenyl phenoxyethyldiethylamine, J. Pharmacol. Exp. Therap. 115:68–73.Google Scholar
  119. Fouts, J. R., and Brodie, B. B., 1956, On the mechanism of drug potentiation by iproniazid (2-isopropyl-1-isonicotinyl hydrazine), J. Pharmacol. Exp. Therap. 116:480–485.Google Scholar
  120. Franklin, M. R., 1974a, The formation of a 455 nm complex during cytochrome P-450-dependent N-hydroxyamphetamine metabolism, Mol. Pharmacol. 10:975–985.Google Scholar
  121. Franklin, M. R., 1974b, Complexes of metabolites of amphetamines with hepatic cytochrome P-450, Xenobiotica 5:133–142.Google Scholar
  122. Franklin, M. R., 1974c, Inhibition of the metabolism of N-substituted amphetamines by SKF 525-A and related compounds, Xenobiotica 4:143–150.Google Scholar
  123. Freter, K., Axelrod, J., and Witkop, B., 1957, Studies on the chemical and enzymatic oxidation of lysergic acid diethylamide, J. Am. Chem. Soc. 79:3191–3193.Google Scholar
  124. Friedhoff, A. H., and Goldstein, M., 1962, New developments in metabolism of mescaline and related amines, Ann. N.Y. Acad. Sci. 96:5–12.PubMedGoogle Scholar
  125. Friedhoff, A. J., and Hollister, L. E., 1966, Comparison of the metabolism of 3,4-dimethoxyphenylethylamine and mescaline in humans, Biochem. Pharmacol. 15:269–273.PubMedGoogle Scholar
  126. Friedhoff, A. J., and Schweitzer, J. W., 1971, Amphetamine metabolism in amphetamine psychosis, Pharmakopsych.-Novropsychopharm. 4:76–83.Google Scholar
  127. Friedhoff, A. J., and Van Winkle, E., 1962, Isolation and characterization of a compound from the urine of schizophrenics, Nature (London) 194:897–898.Google Scholar
  128. Fries, W., Kiese, M., and Lenk, W., 1973, Oxidation of polycyclic N-arylacetamides to glycolamides and hydroxamic acids in rabbits, Xenobiotica 3:525–540.PubMedGoogle Scholar
  129. @@Frigerio, A., and Castagnoli, N., Jr. (eds.), 1974, Mass Spectrometry in Biochemistry and Medicine, Raven Press, New York.Google Scholar
  130. Frigerio, A., and Castagnoli, N., Jr. (eds.), 1976, Advances in Mass Spectrometry and Medicine, Vol. I, Spectrum Press, New York.Google Scholar
  131. Frigerio, A., Fanelli, R., Biandrati, P., Passerini, G., Morselli, P. L., and Garattini, S., 1972, Mass spectrometric characterization of carbamazepine-10,11-epoxide, a carbamazepine metabolite isolated from human urine, J. Pharm. Sci. 61:1144–1147.PubMedGoogle Scholar
  132. Frigerio, A., Sossi, N., Belvedere, G., Pamtarotto, C., and Garattini, S., 1976, Identification of desmethylcyproheptadine-10,11-epoxide and other cyproheptadine metabolites in rat and human urine and from rat liver microsomes, in Advances in Mass Spectrometry in Biochemistry and Medicine, Vol. I (Frigerio, A., and Castagnoli, N., Jr., eds.), pp. 109–118, Spectrum Press, New York.Google Scholar
  133. Fujita, T., and Mannering, G. J., 1973, Electron transport compounds of hepatic microsomes, J. Bid. Chem. 248:8150–8156.Google Scholar
  134. Fuller, R. W., and Hines, C. W., 1967, d-Amphetamine levels in brain and other tissues of isolated and aggregated mice, Biochem. Pharmacol. 16:11–16.Google Scholar
  135. Fuller, R. W., Paru, C. J., and Mallory, B. B., 1973, Metabolism of amphetamines and β,β-difluoroamphetamine in phenobarbital-treated rats, Biochem. Pharmacol. 22:2059–2061.PubMedGoogle Scholar
  136. Fuller, R. W., Perry, K. W., Baker, J. C., Parli, C. J., Lee, N., Day, W. A., and Molloy, B. B., 1974, Comparison of the oxime and the hydroxylamine derivatives of 4-chloroamphetamine as depletor of brain 5-hydroxyindoles, Biochem. Pharmacol. 23:3267–3272.PubMedGoogle Scholar
  137. Gal, J., Wright, J., and Cho, A. K., 1976, In vitro metabolism of amphetamine: An apparent enantiomeric interaction, Res. Commun. Chem. Phath. Pharmacol. 15:525–539.Google Scholar
  138. Garattini, S., Marcucci, F., and Mussini, E., 1975, Biotransformation of drugs to pharmacologically active metabolites, in Concepts in Biochemical Pharmacology, Part 3 (Gillette, J. R., and Mitchell, J. R., eds.), pp. 113–130, Springer-Verlag, Berlin.Google Scholar
  139. Gelboin, H. V., 1971, Mechanisms of induction of drug metabolism enzymes, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 421–451, Springer-Verlag, Berlin.Google Scholar
  140. Giarman, N. J., and Freedman, D. X., 1965, Biochemical aspects of the actions of psychotomimetic drugs, Pharmacol. Rev. 17:1–25.PubMedGoogle Scholar
  141. Gielen, J. E., and Nebert, D. W., 1971, Microsomal hydroxylase induction in liver cell culture by phenobarbital, polycyclic hydrocarbons, and p,p′-DDT, Science 172:167–169.PubMedGoogle Scholar
  142. Gill, E. W., Jones, G., and Lawrence, D. V., 1973, Contribution of the metabolite 7-hydroxy-Δ1-tetrahydro cannabinol towards the pharmacological activity of Δ1-tetrahydrocannabinol in mice, Biochem. Pharmacol. 22:175–184.PubMedGoogle Scholar
  143. Gillette, J. R., 1971, Reductive enzymes in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 349–361, Springer-Verlag, Berlin.Google Scholar
  144. Gillette, J. R., 1974, A perspective on the role of chemically reactive metabolites of foreign compounds in toxicity, Biochem. Pharmacol. 23:2785–2794, 2927-2938.PubMedGoogle Scholar
  145. Gillette, J. R., and Mitchell, J.R. (eds.), 1975, Concepts in Biochemical Pharmacology, Part 3, Springer-Verlag, Berlin.Google Scholar
  146. @@Gillette, J. R., Conney, A. H., Cosmides, G. J., Estabrook, R. W., Fouts, J. R., and Mannering, G. J. (eds.), 1969, Microsomes and Drug Oxidations, Academic Press, New York.Google Scholar
  147. Gillette, J. R., Mitchell, J. R., and Brodie, B. B., 1974, Biochemical basis for drug toxicity, Ann. Rev. Pharmacol. 14:271–288.Google Scholar
  148. Gold, M. S., and Ziegler, D. M., 1973, Dimethylaniline N-oxidase and aminopyrine N-demethylase activities of human liver tissue, Xenobiotica 3:179–189.PubMedGoogle Scholar
  149. Goldstein, A., Aronow, L., and Kalman, S. M., 1974, Principles of Drug Action, 2nd ed., pp. 227–300, Wiley, New York.Google Scholar
  150. Goldstein, M., and Anagnoste, B., 1965, The conversion in vivo of D-amphetamine to (+)-p-hydroxynorephedrine, Biochim. Biophys. Acta 107:166–168.PubMedGoogle Scholar
  151. Goldstein, M., McKeregham, M. R., and Lauber, E., 1964, The stereospecificity of the enzymatic amphetamine β-hydroxylation, Biochim. Biophys. Acta 89:191–193.PubMedGoogle Scholar
  152. Gorrod, J. W., 1973a, Differentiation of various types of biological oxidation of nitrogen in organic compounds, Chem. Biol. Interactions 7:289–303.Google Scholar
  153. Gorrod, J. W., 1973b, Metabolism and excretion of amphetamines in man, in Frontiers in Catecholamine Research (Usdin, E., and Snyder, S., eds.), pp. 945–950, Pergamon Press, New York.Google Scholar
  154. Gorrod, J. W., 1976, The formation of an N-hydroxymethyl intermediate in the N-demethylation of N-methylcarbazole in vivo and in vitro, Xenobiotica 6:265–274.PubMedGoogle Scholar
  155. Gorrod, J. W., and Jenner, P., 1975, Metabolic N-oxidation products of aliphatic amines as potential mediators in amine pharmacology, Int. J. Clin. Pharmacol. Biopharm. 12:180–185.PubMedGoogle Scholar
  156. Gorrod, J. W., Temple, D. J., and Beckett, A. H., 1975, The differentiation of N-oxidation and N-dealkylation of N-ethyl-N-methylaniline by rabbit liver microsomes as distinct metabolic routes, Xenobiotica 5:465–474.PubMedGoogle Scholar
  157. Gram, T. E., Rogers, L. A., and Fouts, J. R., 1967, Effect of pretreatment of rabbits with phenobarbital or 3-methylcholanthrene on the distribution of drug-metabolizing enzyme activity in subfractions of hepatic microsomes, J. Pharmacol. Exp. Therap. 157:435–445.Google Scholar
  158. Greenberg, R. S., and Cohen, G., 1973, Tetrahydroisoquinoline alkaloids: stimulated secretion from the adrenal medulla, J. Pharmacol. Exp. Therap. 184:119–128.Google Scholar
  159. Griffith, J. D., Cavanaugh, J. H., and Oates, J. A., 1970, Psychosis induced by the administration of d-amphetamine to human volunteers, in Psychotomimetic Drugs (Efron, D. H., ed.), pp. 287–294, Raven Press, New York.Google Scholar
  160. Groppetti, A., and Costa, E., 1969, Factors affecting the rate of disappearance of amphetamine in rats, Int. J. Neuropharmacol. 8:209–215.PubMedGoogle Scholar
  161. Grover, P. L., 1974, K-Region epoxides of polycyclic hydrocarbons: formation and further metabolism by rat-lung preparation, Biochem. Pharmacol. 23:333–343.PubMedGoogle Scholar
  162. Grover, P. L., and Sims, P., 1973, K-region epoxides of polycyclic hydrocarbons: reactions with nucleic acids and polyribonucleotides, Biochem. Pharmacol. 22:661–666.PubMedGoogle Scholar
  163. Grover, P. L., Hewer, A., and Sims, P., 1971, Epoxides as microsomal metabolites of polycyclic hydrocarbons, FEBS Lett. 18:76–80.PubMedGoogle Scholar
  164. Grover, P. L., Hewer, A., and Sims, P., 1972, The formation of K-region epoxides as microsomal metabolites of pyrene and benzo(a)pyrene, Biochem. Pharmacol. 21:2713–2726.PubMedGoogle Scholar
  165. Grover, P. S., Hewer, A., and Sims, P., 1974, Metabolism of polycyclic hydrocarbons by rat-lung preparations, Biochem. Pharmacol. 23:323–332.PubMedGoogle Scholar
  166. Groves, J. T., and Van der Puy, M., 1974, Stereospecific aliphatic hydroxylation by an iron based oxidant, J. Am. Chem. Soc. 96:5274–4275.Google Scholar
  167. Gunne, L.-M., and Anggard, E., 1973, Amphetamine metabolism in amphetamine-induced psychosis, in Frontiers in Catecholamine Research (Usdin, E., and Snyder, S., eds.), pp. 983–985, Raven Press, New York.Google Scholar
  168. Gunne, L.-M., and Galland, L., 1967, Stereoselective metabolism of amphetamine, Biochem. Pharmacol. 16:1371–1477.Google Scholar
  169. Haefely, W., Bartholini, G., and Pletcher, A., 1976, Monoaminergic drugs: General pharmacology, Pharmacol. Therap. B 2:185–218.Google Scholar
  170. Hald, J., and Jacobsen, E., 1948, A drug sensitising the organism to ethyl alcohol, Lancet 2:1001–1004.PubMedGoogle Scholar
  171. Hamilton, G. H., 1964, Oxidation by molecular oxygen. II. The oxygen atom transfer mechanism for mixed-function oxidases and the model for mixed-function oxidases, J. Am. Chem. Soc. 86:3391–3392.Google Scholar
  172. Hansch, C., 1972, Quantitative relationships between lipophilic character and drug metabolism, Drug. Metab. Rev. 1:1–13.Google Scholar
  173. Harley-Mason, J., Laird, A. H., and Smythies, J. R., 1958, I. The metabolism of mescaline in the human, II. Delayed clinical reactions to mescaline, Confin. Neurol. Base 1 18:152–155.Google Scholar
  174. Hartley, R., and Smith, J. A., 1973, Formation in vitro of N-acetyl-3,4-dimethoxyphenylethylamine by pineal hydroxyindole-O-methyl transferase, Biochem. Pharmacol. 22:2425–2428.PubMedGoogle Scholar
  175. Harvey, R. G., Goh, S. H., and Cortez, C., 1975, K-Region oxides and related oxidized metabolites of carcinogenic aromatic hydrocarbons, J. Am. Chem. Soc. 97:3468–3479.PubMedGoogle Scholar
  176. Hathway, D. E. (senior reporter), 1975, Foreign Compound Metabolism in Mammals Vol. 3, The Chemical Society, London.Google Scholar
  177. Heidelberger, C., and Iype, P. T., 1967, Malignant transformation in vitro by carcinogenic hydrocarbons, Science 155:214–217.PubMedGoogle Scholar
  178. Hewick, D. S., and Fouts, J. R., 1970, The metabolism in vitro and hepatic microsomal interactions of some enantiomeric drug substrates, Biochem. J. 117:833–841.PubMedGoogle Scholar
  179. Hirtz, J., 1976, The Fate of Drugs in the Organism, Marcel Dekker, New York.Google Scholar
  180. Ho, B. T., Estevez, V., and Fritchie, G. E., 1971a, The fate of 2,5-dimethoxy-4-methylphenylamphetamine (STP, DOM) in monkey and rat brains, Brain Res. 29:166–169.PubMedGoogle Scholar
  181. Ho, B. T., Estevez, V., Tansey, L. W., Englert, L. F., Creaven, P. J., and McIssac W. M., 1972b, Analogs of amphetamine. 5. Studies of excretory metabolites of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats, J. Med. Chem. 14:158–160.Google Scholar
  182. Ho, B. T., Pong, S. F., Browne, R. G., and Walker, K. E., 1973, Acetylation of mescaline in rat brains, Experientia 29:275–277.PubMedGoogle Scholar
  183. Hoffer, A., Smith, C., Callbeck, M. J., and Mahon, M., 1959, Physiological response to LSD and its relation to adrenochrome levels, J. Clin. Exp. Psychopath. 20:125–134.PubMedGoogle Scholar
  184. Holmes, J. C., and Rutledge, C. O., 1976, Effects of the d-and l-isomers of amphetamine on uptake, release and catabolism of norepi, DA, and 5-HT in serial regions of rat brain, Biochem. Pharmacol. 25:447–451.PubMedGoogle Scholar
  185. Holtzman, J., Gillette, J. R., and Milne, G. W. A., 1967, The metabolic products of naphthalene in mammalian species, J. Am. Chem. Soc. 89:6341–6344.PubMedGoogle Scholar
  186. Horning, M. G., Butler, C. M., Stafford, M., Stillwell, R. N., Hill, R. M., Zion, T. E., Harvey, D. J., and Stillwell, W. G., 1976, Metabolism of drugs by the epoxide-diol pathway, in Advances in Mass Spectrometry in Biochemistry and Medicine, Vol. I (Frigerio A., and Castagnoli, N., eds.), pp. 91–108, Spectrum Press, New York.Google Scholar
  187. Hucker, H. B., 1973, Phenylacetone oxime—An intermediate in amphetamine deamination, Drug. Metab. Disp. 1:332–336.Google Scholar
  188. Hucker, H. B., Michnewicz, B. M., and Rhodes, R. E., 1971, Phenylacetone oxime—An intermediate in the oxidative deamination of amphetamine, Biochem. Pharmacol. 20:2123–2128.PubMedGoogle Scholar
  189. Hucker, H. B., Balletto, A. J., Demetriades, J., Arison, B. H., and Zacchei, A. G., 1974, Epoxide metabolites of protriptyline in rat urine, Drug Metab. Disp. 3:80–84.Google Scholar
  190. Huszti, Z., and Borsy, J., 1966, Differences between aminé oxidases deaminating mescaline and the structurally related 3,4-dimethoxyphenylethylamine, Biochem. Pharmacol. 15:475–480.PubMedGoogle Scholar
  191. Hutson, D. H., 1975a, Mechanisms of biotransformation: other oxidative routes of metabolism, in Foreign Compound Metabolism in Mammals, Vol. 3 (Hathway, D. E., senior reporter), pp. 512–520, The Chemical Society, London.Google Scholar
  192. Hutson, D. H., 1975b, Mechanisms of biotransformation: hydrolysis, in Foreign Compound Metabolism in Mammals, Vol. 3 (Hathway, D. E., senior reporter), pp. 522–523, The Chemical Society, London.Google Scholar
  193. Hutson, D. H., 1975c, Mechanisms of biotransformation: conjugation, in Foreign Compound Metabolism in Mammals, Vol. 3 (Hathway, D. E., senior reporter), pp. 533–549, The Chemical Society, London.Google Scholar
  194. Idänpään-Heikkila, J. E., and McIssac, W. M., 1970, 2,5-Dimethoxy-4-methylamphetamine—tissue, distribution and neurochemical action, Biochem. Pharmacol. 19:935–937.PubMedGoogle Scholar
  195. Innes, I. R., and Nickerson, M., 1975, Norepinephrine, epinephrine, and the sympathomimetic amines, in The Pharmacological Basis of Therapeutics, 5th ed. (Goodman, L. S., and Gilman, A., eds.), pp. 496–499, Macmillan, New York.Google Scholar
  196. Israili, Z. H., Cucinell, S. A., Vaught, J., Davis, E., Lesser, J. M., and Dayton, P. G., 1973, Man and experimental animals: Formation of N-hydroxy metabolites, J. Pharmacol. Exp. Therap. 187:138–151.Google Scholar
  197. James, R. C., and Franklin, M. R., 1975, Comparisons of the formation of cytochrome P-450 complexes absorbing at 455 nm in rabbit and rat microsomes, Biochem. Pharmacol. 24:835–838.PubMedGoogle Scholar
  198. Jerina, D. M., and Daly, J. W., 1974, Arene oxides: A new aspect of drug metabolism, Science 185:573–582.PubMedGoogle Scholar
  199. Jerina, D. M., Daly, J. W., Witkop, B., Zalzman-Nirenberg, P., and Udenfriend, S., 1970, 1,2-Naphthalene oxide as an intermediate in the microsomal hydroxylation of naphthalene, Biochemistry 9:147–156.PubMedGoogle Scholar
  200. Jerina, D. M., Daly, J. W., and Witkop, B., 1971, Migration of substituents during hydroxylation of aromatic substrates (NIH shift). Oxidations with peroxytrifluoroacetic acid, Biochemistry 10:366–372.PubMedGoogle Scholar
  201. Jollow, D. J., Mitchell, J. R., Potter, W. Z., Davis, D. C., Gillette, J. R., and Brodie, B. B., 1973, Acetaminophen-induced hepatic necrosis II. Role of covalent binding in vivo, J. Pharmacol. Exp. Therap. 187:175–202.Google Scholar
  202. Jollow, D. J., Thorgeirsson, S. S., Potter, W. Z., Hashimoto, M., and Mitchell, J. R., 1974a, Acetaminophen-induced hepatic necrosis VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen, Pharmacology 12:251–271.PubMedGoogle Scholar
  203. Jollow, D. J., Mitchell, J. R., Zampaglione, N., and Gillette, J. R., 1974b, Bromobenzene-induced hepatic necrosis: Protective role of glutathione and evidence for 3,4-bromobenzene oxide as the hepatic metabolite, Pharmacology 11:151–169.PubMedGoogle Scholar
  204. Jonsson, J. A., 1974, Hydroxylation of amphetamine to parahydroxyamphetamine by rat liver microsomes, Biochem. Pharmacol. 23:3191–3197.PubMedGoogle Scholar
  205. Jonsson, L.-E., and Gunne, L.-M., 1970, Clinical studies of amphetamine psychosis, in Amphetamines and Related Compounds (Costa, E., and Garattini, S., eds.), pp. 929–936, Raven Press, New York.Google Scholar
  206. Jori, A., and Caccia, S., 1974, Distribution of amphetamine and its hydroxylated metabolites in various areas of the rat brain, J. Pharm. Pharmacol. 26:746–748.PubMedGoogle Scholar
  207. Kapadia, G. J., Rao, G. S., Leete, E., Fayez, M. B. E., Vaishnav, Y. N., and Fales, H. M., 1970, On the origin of carbon 1 in tetrahydroisoquinoline alkaloids, J. Am. Chem. Soc. 92:6943–6951.PubMedGoogle Scholar
  208. Kasperek, G. J., and Bruice, T. C., 1972, The mechanism of the aromatization of arene oxides, J. Am. Chem. Soc. 94:198–202.Google Scholar
  209. Kaufman, S., and Friedman, S., 1965, Dopamine-β-hydroxylase, Pharmacol. Rev. 17:71–100.PubMedGoogle Scholar
  210. Kaufman, S., Bridges, W. F., Eisenberg, F., and Friedman, S., 1967, The source of oxygen in phenylalanine hydroxylase and dopamine-β-hydroxylase catalyzed reactions, Biochem. Biophys. Res. Commun. 9:497–502.Google Scholar
  211. Keberle, H., Hoffmann, K., and Bernhard, K., 1962, The metabolism of glutethimide (Doriden), Experientia 18:105–111.PubMedGoogle Scholar
  212. Keberle, H., Riess, W., and Hoffman, K., 1963, Stereospecific metabolism of optical antipodes of α-phenyl-α-ethyl glutarimide (Doriden), Arch. Int. Pharmacodyn. Therap. 142:117–124.Google Scholar
  213. Keller, J. W., and Heidelberger, C., 1976, Polycyclic K-region arene oxides products and kinetic of solvolysis, J. Am. Chem. Soc. 98:2228–2236.Google Scholar
  214. Keller, R. E., and Ellenbogen, W. C., 1952, The determination of D-amphetamine in body fluids, J. Pharmacol. Exp. Therap. 106:77–82.Google Scholar
  215. Kiese, M., 1966, The biochemical production of ferrihemoglobin-forming derivatives from aromatic amines, and mechanisms of ferrihemoglobin formation, Pharmacol. Rev. 18:1091–1161.PubMedGoogle Scholar
  216. Kiese, M., and Lenk, W., 1973, ω and (ω-1)-hydroxylation of 4-chloropropronanilide by rabbits and rabbit liver microsomes, Biochem. Pharmacol. 22:2565–2574.Google Scholar
  217. Kiese, M., and Renna, G., 1976, Mechanism of the autocatalytic formation of ferrihemoglobin by N,N-dimethylaniline-N-oxide, Chem. Biol. Interaction 12:415–424.Google Scholar
  218. King, C. M., and Phillips, B., 1972, Mechanisms of introduction of fluorenylamine substituents into nucleic acid by rat liver, Proc. Am. Assoc. Cancer Res. 13:43.Google Scholar
  219. Kinoshita, N., Shears, B., and Gelboin, H. V., 1973, K-Region and non-K-region metabolism of benzo(a)pyrene by rat liver microsomes, Cancer Res. 33:1937–1944.PubMedGoogle Scholar
  220. Knoll, J., 1970, Psychotomimetic effects of amphetamines, in Amphetamines and Related Compounds (Costa, E., and Garattini, S., eds.), pp. 761–780, Raven Press, New York.Google Scholar
  221. Kopin, I. J., 1972, Metabolic degradation of catecholamines. The relative importance of different pathways under physiological conditions and after administration of drugs, in Catecholamines (Blaschko, H., and Muscholl, E., eds.), pp. 270–282, Springer-Verlag, Berlin.Google Scholar
  222. Kostrzewa, R. M., and Jacobowitz, D. M., 1974, Pharmacological actions of 6-hydroxydopamine, Pharmacol. Rev. 26:199–288.PubMedGoogle Scholar
  223. Kupfer, D., and Rosenfeld, J., 1973, A sensitive radioactive assay for hexobarbital hydroxylase in hepatic microsomes, Drug Metab. Disp. 1:760–765.Google Scholar
  224. La Du, B. N., and Shady, H., 1971, Esterases of human tissues, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 477–499, Springer-Verlag, Berlin.Google Scholar
  225. La Du, B. N., Mandel, G. G., and Way, E. L., (eds.), 1971, Fundamentals of Drug Metabolism and Drug Disposition, Williams and Wilkins, Baltimore, Maryland.Google Scholar
  226. Lal, H., Puri, S. K., and Fuller, G. C., 1970, Inhibition of hepatic hexobarbital metabolism by dextroamphetamine, Psychopharmacologia 16:395–398.PubMedGoogle Scholar
  227. Leemann, H. G., and Fabbri, S., 1959, Über die absolute Kunfiguration der Lysergsäure, Helv. Chim. Acta 42:2696–2709.Google Scholar
  228. Leibman, K. C., 1971, Reduction of ketones in liver cytosol, Xenobiotica 1:97–104.PubMedGoogle Scholar
  229. Levin, W., Jacobson, M., Sernatinger, E., and Kuntzman, R., 1973, Breakdown of cytochrome P-450 heme by secobarbital and other allyl-containing barbituates, Drug Metab. Disp. 1:275–283.Google Scholar
  230. Lewander, T., and Jonssan, J., 1973, Drugs and certain conditions interfering with the metabolism and excretion of amphetamine in the rat, in Psychopharmacol. Sex. Disord. Drug Abuse, Proc. Symp. Congr. Coll. Int. Neuropsychopharmacol., 8th ed. (Ban, T. A., ed.), pp. 577–583, North-Holland, Amsterdam.Google Scholar
  231. Lhoëst, G., Razzouk, C., and Mercier, M., 1976, Biological implications of the reaction possibilities of the proximate carcinogenic compounds, N-hydroxy-2-fluorenylacetamide, Biomed. Mass Spec. 3:21–27.Google Scholar
  232. Lipscomb, J. D., and Gunsalus, I. C., 1973, Structural aspects of the active site of cytochrome P-450, Drug Metab. Disp. 1:1–5.Google Scholar
  233. Locke, R. K., and Mayer, V. M., 1974, Physical evidence for the oxidative demethylation in vitro of 1-naphthyl-N-methyl carbamate by the Udenfriend chemical hydroxylation system, Biochem. Pharmacol. 23:1979–1984.PubMedGoogle Scholar
  234. Lu, A. Y. H., West, S. B., Ryan, D., and Levin, W., 1973, Characterization of partially purified cytochromes P-450 and P-448 from rat liver microsomes, Drug Metab. Disp. 1:29–37.Google Scholar
  235. Malmfors, T., and Thoenen, H., (eds.), 1971 6-Hydroxydopamine and Catecholamine Neurons, North-Holland, Amsterdam.Google Scholar
  236. Mandel, L. R., Rosegay, A., Walker, R. W., Vanden Heuvel, W. J. A., and Rokaclz, J., 1974, 5-Methyltetrahydrofolic acid as a mediator in the formation of pyridoindoles, Science 186:741–743.PubMedGoogle Scholar
  237. Mannering, G. J., 1971, Inhibition of drug metabolism, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 452–476, Springer-Verlag, Berlin.Google Scholar
  238. Mansuy, D., Beaune, P., Chottard, J. C., Bartoli, J. F., and Gans, P., 1976, The nature of the “455 nm absorbing complex” formed during cytochrome P-450 dependent oxidative metabolism of amphetamine, Biochem. Pharmacol. 25:609–612.PubMedGoogle Scholar
  239. Marckel, R. P., and Harrison, S. D., 1974, Inability of rat brain homogenate to oxidize amphetamine, Biochem. Pharmacol. 23:1146–1147.Google Scholar
  240. Marquardt, G. M., and DiStefano, V., 1974, The hepatic microsomal metabolism of β-3,4-methylenedioxyamphetamine (MDA), Life Sci. 15:1603–1610.PubMedGoogle Scholar
  241. Mason, H. S., 1957, Mechanisms of oxygen metabolism, Advan. Enzymol. 19:79–233.Google Scholar
  242. Mason, H. S., Fowlke, W. L., and Peterson, E., 1955, Oxygen transfer and electron transport by the phenolase complex, J. Am. Chem. Soc. 77:2914–2915.Google Scholar
  243. Matin, S. B., Callery, P. S., Zweig, J. S., O’Brien, A., Rapoport, R., and Castagnoli, N., Jr., 1974, Stereochemical aspects and metabolite formation in the in vivo metabolism of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane, J. Med. Chem. 17:877–882.PubMedGoogle Scholar
  244. Maynert, E. W., Foreman, R. L., and Watabe, T., 1970, Epoxides as obligatory intermediates in the metabolism of olefins to glycols, J. Biol. Chem. 245:5234–5238.PubMedGoogle Scholar
  245. McGraw, N. P., Callery, P. S., and Castagnoli, N., Jr., 1977, The in vitro stereoselective metabolism of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane: An apparent enantiometic interaction, J. Med. Chem. 20:185–189.PubMedGoogle Scholar
  246. McKennis, H., Jr., Turnbull, L. B., Bowman, E. R., and Schwartz, S. L., 1962, A corrected structure of a ketoamide arising from the metabolism of (-)-nicotine, J. Am. Chem. Soc. 84:4598–4599.Google Scholar
  247. McKennis, H., Jr., Schwartz, S. L., and Bowman, E. R., 1964, Alternate routes in the metabolic degradation of the pyrrolidine ring of nicotine, J. Biol. Chem. 239:3990–3996.PubMedGoogle Scholar
  248. McMahon, R. E., 1966, Microsomal dealkylation of drugs: Substrate specificity and mechanism, J. Pharm. Sci. 55:457–466.Google Scholar
  249. McMahon, R. E., 1970, Drug metabolism, in Medicinal Chemistry, Part 1, 3rd ed. (A. Burger, ed.), pp. 50–63, Wiley (Interscience), New York.Google Scholar
  250. McMahon, R. E., 1971, Enzymatic oxidation and reduction of alcohols, aldehydes and ketones, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 500–517, Springer-Verlag, Berlin.Google Scholar
  251. McMahon, R. E., Culp, H. W., and Occolowtz, J. C., 1969a, Studies on the hepatic microsomal N-dealkylation raaction. Molecular oxygen on the source of the oxygen atom, J. Am. Chem. Soc. 91:3389–3390.Google Scholar
  252. McMahon, R. E., Craig, J. C., and Pereira, W. E., Jr., 1969b, The microsomal oxygenation of ethylbenzene: Isotopic, stereochemical and induction studies, Arch. Biochem. 132:575–577.PubMedGoogle Scholar
  253. Mechoulam, R., Varconi, H., Ben-Zvi, Z., Edery, H., and Grunfeld, U., 1972, Synthesis and biological activity of five tetrahydrocannabinol metabolites, J. Am. Chem. Soc. 94:7930–7931.PubMedGoogle Scholar
  254. Mechoulam, R., McCallum, N. K., and Burstein, S., 1976, Recent advances in the chemistry and biochemistry of Cannabis, Chem. Rev. 76:75–109.Google Scholar
  255. Metzler, M., 1976, Metabolic activation of diethylstilbestrol: Indirect evidence for the formation of a stilbene oxide intermediate in hamster and rat, Biochem. Pharmacol. 24:1449–1453.Google Scholar
  256. Michalopoulos, G., Sattler, C. A., Sattler, G. L., and Pitot, H. C., 1976, Cytochrome P-450 induction by phenobarbital and 3-methylcholanthrene in primary culture of hepatocytes, Science 193:907–909.PubMedGoogle Scholar
  257. Midha, K. K., 1974, Identification of two in vitro metabolites of 3,4-methylenedioxyamphetamine by gas-liquid chromatography-mass spectrometry, J. Chromatogr. 101:210–214.PubMedGoogle Scholar
  258. Miller, E. C., and Miller, J. A., 1966, Mechanisms of chemical carcinogenesis: Nature of proximate carcinogens and interactions with macromolecules, Pharmacol. Rev. 18:805–838.PubMedGoogle Scholar
  259. Miller, E. C., Miller, J. A., and Enomoto, M., 1964, The comparative carcinogenicities of 2-acetylaminofluorene and its N-hydroxy metabolite in mice, hamsters, and guinea pigs, Cancer Res. 24:2018–2031.PubMedGoogle Scholar
  260. Miller, J. A., 1970, Carcinogenesis by chemicals: An overview, Cancer Res. 30:559–576.PubMedGoogle Scholar
  261. Miller, J. A., and Miller, E. C., 1969, Metabolic activation of carcinogenic aromatic amines and amides via N-hydroxylation and N-hydroxyesterification and its relationship to ultimate carcinogens as electrophilic reagents, in Jerusalem Symp. Quantum Chem. Biochem. Vol. I, pp. 237–261, Israel Academy of Sciences and Humanities, Jerusalem.Google Scholar
  262. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., and Brodie, B. B., 1973a, Acetaminophen-induced hepatic necrosis. 1. Role of drug metabolism, J. Pharmacol. Exp. Therap. 187:185–194.Google Scholar
  263. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Gillette, J. R., and Brodie, B. B., 1973b, Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione, J. Pharmacol. Exp. Therap. 187:211–217.Google Scholar
  264. Mitchell, J. R., Potter, W. Z., Hinson, J. A., Snodgrass, W. R., Timbrell, J. A., and Gillette, J. R., 1975, Toxic Drug Reactions, in Concepts in Biochemical Pharmacology, Part 3 (Gillette, J. R., and Mitchell, J. R., eds.), pp. 383–419, Springer-Verlag, Berlin.Google Scholar
  265. Mitoma, C., 1970, Metabolic studies on trimethoxyamphetamines (34965), Proc. Soc. Exp. Biol. Med. 134:1162–1164.PubMedGoogle Scholar
  266. Mitoma, C., Yasuda, D. M., Tagg, T., and Tanabe, M., 1967, Effect of deuteration of the O-CH3 group on the enzymatic demethylation of O-nitroanisole, Biochim. Biophys. Acta 136:566–567.PubMedGoogle Scholar
  267. Mitra, C., and Guha, S. R., 1973, Amphetamine oxidation in rat brain, Biochem Pharmacol. 22:651–657.PubMedGoogle Scholar
  268. Mokrasch, L. C., and Stevenson, I., 1962, The metabolism of mescaline with a note on correlations between metabolism and psychological effects, J. Nerv. Ment. Dis. 129:177–183.Google Scholar
  269. Moro-oka, Y., and Foote, C. S., 1976, Chemistry of Superoxide ion. 1. Oxidation of 3,5-di-tert-butylcatechol with KO2, J. Am. Chem. Soc. 98:1510–1514.PubMedGoogle Scholar
  270. Murphy, P., 1973, Enzymatic oxidation of nicotine to nicotine Δ1,5 iminium ion. A newly discovered intermediate in the metabolism of nicotine, J. Biol. Chem. 248:2796–2800.PubMedGoogle Scholar
  271. Musacchio, J. M., and Goldstein, M., 1967, The metabolism of mescaline-14C in rats, Biochem. Pharmacol. 16:963–970.PubMedGoogle Scholar
  272. Muscholl, E., 1972, Adrenergic false transmitters, in Catecholamines (Blaschko, H., and Muscholl, E., eds.), pp. 618–660, Springer-Verlag, Berlin.Google Scholar
  273. Naranjo, C., Shulgin, A., and Sargent, T., 1967, Evaluation of 3,4-methylenedioxyamphetamine (MDA) as an adjunct to psychotherapy, Med. Pharmacol. Exp. 17:359–364.Google Scholar
  274. Neff, N., Rossi, G. V., Chase, G. D., and Rabinowitz, J. L., 1964, Distribution and metabolism of mescaline-C14 in the cat brain, J. Pharmacol. Exp. Therap. 144:1–7.Google Scholar
  275. Nguyen, T.-L., Gruenke, L. D., and Castagnoli, N., Jr., 1976, Metabolic N-demethylation of nicotine. Trapping of a reactive iminium species with cyanide ion, J. Med. Chem. 19:1168–1169.PubMedGoogle Scholar
  276. Nichols, D. E., Barfknecht, C. F., and Rusterholz, D. B., 1973, Asymmetric synthesis of psychotomimetic phenylisopropylamines, J. Med. Chem. 16:480–483.PubMedGoogle Scholar
  277. Niwaguchi, T., Inoue, T., and Nakahara, Y., 1974a, Studies on enzymatic dealkylation of D-lysergic acid diethylamide (LSD), Biochem. Pharmacol. 23:1073–1078.PubMedGoogle Scholar
  278. Niwaguchi, T., Inoue, T., and Sakai, T., 1974b, Studies on the in vitro metabolism of compounds related to LSD, Biochem. Pharmacol. 23:3063–3066.PubMedGoogle Scholar
  279. Oesch, F., 1973, Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds, Xenobiotica 3:305–337.PubMedGoogle Scholar
  280. Oesch, F., Jerina, D. M., and Daly, J. W., 1971, Substrate specificity of hepatic epoxide hydrase in microsomes and in a purified preparation: Evidence for homologous enzymes, Arch. Biochem. Biophys. 144:253–261.PubMedGoogle Scholar
  281. Oesch, F., Thuenen, H., and Fahrlaender, H., 1974, Epoxide hydrase in human liver biopsy specimens, assay and properties, Biochem. Pharmacol. 23:1307–1317.PubMedGoogle Scholar
  282. Omura, T., and Sato, R., 1964, The carbon monoxide-binding pigment of liver microsomes, I. Evidence for its hemoprotein nature, J. Biol. Chem. 239:2370–2378.PubMedGoogle Scholar
  283. Ono, T., and Bloch, K., 1975, Solubilization and partial characterization of rat liver squalene epoxidase, J. Biol. Chem. 250:1571–1579.PubMedGoogle Scholar
  284. Orme-Johnson, W. H., and Ziegler, D. M., 1965, Alcohol mixed functions. Oxidase activity of mammalian liver microsomes, Biochem. Biophys. Res. Commun. 21:78–82.PubMedGoogle Scholar
  285. Parke, D. V., 1968, The Biochemistry of Foreign Compounds, p. 218, Pergamon Press, Oxford.Google Scholar
  286. Parli, C. J., and McMahon, R. E., 1973, The mechanism of microsomal deamination: Heavy isotope studies, Drug Metab. Disp. 1:337–341.Google Scholar
  287. Parli, C. J., Wang, N., and McMahon, R. E., 1971, The mechanism of the oxidation of d-amphetamine by rabbit liver oxygenase. Oxygen-18 studies, Biochem. Biophys. Res. Commun. 43:1204–1209.PubMedGoogle Scholar
  288. Pittman, K. A., 1970, Human metabolism of orally administered pentazocine, Biochem. Pharmacol. 19:1833–1836.PubMedGoogle Scholar
  289. Pittman, K. A., Rosi, D., Cherniak, R., Merola, A. J., and Conway, W. D., 1969, Metabolism in vitro and in vivo pentazocine, Biochem. Pharmacol. 18:1673–1678.PubMedGoogle Scholar
  290. Poirier, L. A., and Weisburger, J. H., 1974, Enzymatic reduction of carcinogenic aromatic nitro compounds by rat and mouse liver functions, Biochem. Pharmacol. 23:661–669.PubMedGoogle Scholar
  291. Potter, W. Z., Davis, D. C., Mitchell, J. R., Jollow, D. J., Gillette, J. R., and Brodie, B. B., 1973, Acetaminophen-induced hepatic necrosis, III. Cytochrome P-450 mediated covalent binding in vitro, J. Pharmacol. Exp. Therap. 187:203–210.Google Scholar
  292. Potter, W. Z., Thorgeirsson, S. S., Jollow, D. J., and Mitchell, J. R., 1974, Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters, Pharmacology 12:129–143.PubMedGoogle Scholar
  293. Racker, E., 1949, Aldehyde dehydrogenase, a diphosphopyridine nucleotide-linked enzyme, J. Biol. Chem. 177:883–892.PubMedGoogle Scholar
  294. Radomski, J. L., and Brill, E., 1970, Bladder cancer induction by aromatic amines: Role of N-hydroxy metabolites, Science 167:992–993.PubMedGoogle Scholar
  295. Radomski, J. L., and Brill, E., 1971, The role of N-oxidation products of aromatic amines in the induction of bladder cancer in the dog, Arch. Toxikol. 28:1461–1467.Google Scholar
  296. Rajagopalan, K. V., Fridovich, I., and Handler, P., 1962, Hepatic aldehyde oxidase. I. Purification and properties, J. Biol. Chem. 237:922–928.PubMedGoogle Scholar
  297. Rentsch, G., and Johnston, A., 1976, The effect of prolonged administration of allylisopropylacetylurea to rats on cytochrome P-450 and other liver haemoproteins, Xenobiotica 6:151–158.PubMedGoogle Scholar
  298. Riceberg, L. J., Simon, M., Van Vunakis, H., and Abeles, R. H., 1975, Effect of aminoacetronitrile, an amine oxidase inhibitor, on mescaline metabolism in the rabbit, Biochem. Pharmacol. 24:119–125.PubMedGoogle Scholar
  299. Rommelspacher, H., Honecker, H., Schulze, G., and Strauss, S. M., 1974, The hydroxylation of d-amphetamine by liver microsomes of the male rat, Biochem. Pharmacol. 23:1065–1071.PubMedGoogle Scholar
  300. Rowland, M., and Beckett, A. H., 1966, The amphetamines: clinical and pharmacokinetic implications of recent studies on assay procedure and urinary excretion in man, Arzneim.-Forsch. 16:1369–1373.Google Scholar
  301. Roy, A. B., 1971, Sulphate conjugation enzymes, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 536–563, Springer-Verlag, Berlin.Google Scholar
  302. Saavedra, J. M., and Axelrod, J., 1972, Psychotomimetic N-methylated tryptamines: Formation in brain in vivo and in vitro, Science 175:1365–1370.PubMedGoogle Scholar
  303. Sadèe, W., Garland, W., and Castagnoli, N., Jr., 1971, Microsomal 3-hydroxylation of 1,4-benzodiazepines, J. Med. Chem. 14:643–645.PubMedGoogle Scholar
  304. Sandler, M., Carter, S. B., Hunter, K. R., and Stern, G. M., 1973, Tetrahydroisoquinoline alkaloids: in vivo metabolites of L-dopa in man, Nature 241:439–443.PubMedGoogle Scholar
  305. Saner, A., and Thoenen, H., 1971, Model experiments on the molecular mechanism of action of 6-hydroxydopamine, Mol. Pharmacol. 7:147–154.PubMedGoogle Scholar
  306. Sankar, D. V. S., 1975, LSD—A Total Study, pp. 255–265, P.J.D. Pub., Ltd., Westbury, New York.Google Scholar
  307. Sargent, T., III, Shulgin, A. T., and Kusubov, N., 1976, Quantitative measurement of demethylation of 14C-methoxyl labeled DMPEA and TMA-2 in rats, Psychopharmacol. Commun. 2:199–206.PubMedGoogle Scholar
  308. Sato, R., Haruhiku, S., and Imai, Y., 1973, Partial purification and some spectral properties of hepatic microsomal P-450, Drug Metab. Disp. 1:6–11.Google Scholar
  309. Schmidt, H.-L., Möller, M. R., and Weber, N., 1973, Über den Einfluss von Substituenten auf die mikrosomale Entalkylierung aromatischer N-, O-, und S-Alkylverbindungen, Biochem. Pharmacol. 22:2989–2996.PubMedGoogle Scholar
  310. Schwartz, M. A., and Postma, E., 1968, Metabolism of diazepam in vitro, Biochem. Pharmacol. 17:2443–2449.PubMedGoogle Scholar
  311. Segal, D. S., 1975, Behavioral characterization of d-and l-amphetamines: Neurochemical implications, Science 190:475–477.PubMedGoogle Scholar
  312. Seiler, N., and Demisch, L., 1974a, Oxidative metabolism of mescaline in the central nervous system—III. Side chain degradation of mescaline and formation of 3,4,5-trimethoxybenzoic acid in vivo, Biochem. Pharmacol. 23:259–271.PubMedGoogle Scholar
  313. Seiler, N., and Demisch, L., 1974b, IV. In vivo metabolism of mescaline and 2,3,4-trimethoxyphenylethylamine, Biochem. Pharmacol. 23:273–287.PubMedGoogle Scholar
  314. Selkirk, J. K., Huberman, E., and Heidelberger, C., 1971, An epoxide is an intermediate in the microsomal metabolism of the chemical carcinogen, dibenz(a,b)anthracene, Biochem. Biophys. Res. Commun. 43:1010–1016.PubMedGoogle Scholar
  315. Senoh, S., Witkop, B., Creveling, C. R., and Udenfriend, S., 1959, 2,4,5-Tri-hydroxyphenethylamine, a new metabolite of 3,4-dihydroxyphenethylamine, J. Am. Chem. Soc. 81:1768–1769.Google Scholar
  316. Sever, P. S., Dring, L. G., and Williams, R. T., 1973a, The metabolism of hydroxyamphetamines in man and animals: 4′-hydroxy(14C)amphetamine (paredrine), Biochem. Soc. Trans. 1:1158–1159.Google Scholar
  317. Sever, P. S., Caldwell, J., Dring, L. G., and Williams, R. T., 1973b, Metabolism of amphetamine in dependent subjects, Eur. J. Clin. Pharmacol. 6:177–180.PubMedGoogle Scholar
  318. Sever, P. S., Dring, L. G., and Williams, R. T., 1976, Urinary metabolites of p-hydroxyamphetamine in man, rat and guinea pig, Xenobiotica 6:345–353.PubMedGoogle Scholar
  319. Shah, N. S., and Himmich, H. E., 1971, Study with mescaline-8-C14 in mice: effect of amine oxidase inhibitors on metabolism, Neuropharmacology 10:547–556.PubMedGoogle Scholar
  320. @@Shugar, D. (ed.), 1969, Biochemical aspects of antimetabolites and of drug hydroxylation, in Fed. Eur. Biochem. Soc. Proc. 16, Academic Press, New York.Google Scholar
  321. Shulgin, A. T., 1964, Psychotomimetic amphetamines. II. Methoxy 3,4-dialkoxyamphetamines, Experientia 20:366–367.PubMedGoogle Scholar
  322. Shulgin, A. T., 1973, Stereospecific requirements for hallucinogenesis, J. Pharm. Pharmacol. 25:271–272.PubMedGoogle Scholar
  323. Shulgin, A. T., Sargent, T., and Naranjo, C., 1969, Structure-activity relationships of one-ring psychotomimetics, Nature 221:537–541.PubMedGoogle Scholar
  324. Sims, P., Grover, P. L., Kuroki, T., Huberman, E., Marquardt, H., Selkirk, J. K., and Heidelberger, C., 1973, The metabolism of benz(a)anthracene and dibenz(a,h)anthracene and their related “K-region” epoxides, cis-dihydrodiols and phenols by hamster embryo cells, Biochem. Pharmacol. 22:1–9.PubMedGoogle Scholar
  325. Sisenwine, S. F., Tio, C. G., Shrader, S. R., and Roelius, H. W., 1970, The biotransformation of protriptyline in man, pig and dog, J. Pharmacol. Exp. Therap. 175:51–59.Google Scholar
  326. Sjoerdsma, A., and Von Studnitz, W., 1963, Dopamine-β-oxidase activity in man, using hydroxyamphetamine as substrate, Br. J. Pharmacol. 20:278–284.Google Scholar
  327. Slotta, K. H., and Muller, J., 1936, On the catabolism of mescaline and mescaline-like substances in the organism, Hoppe-Seyler’s Z. 238:14–22.Google Scholar
  328. Smith, J. N., Smithies, R. H., and Williams, R. T., 1954, Studies in detoxification: 59. The metabolism of alkybenzenes. The biological reduction of ketones derived from alkylbenzenes, Biochem. J. 57:74–76.PubMedGoogle Scholar
  329. Smith, R. L., and Dring, L. G., 1970, Patterns of metabolism of β-phenylisopropylamines in man and other species, in Amphetamines and Related Compounds (Costa, E., and Garattini, S., eds.), pp. 121–139, Raven Press, New York.Google Scholar
  330. Smythies, J. R., 1963, Schizophrenia: Chemistry, Metabolism and Treatment, pp. 1–86, Charles C. Thomas, Springfield, Illinois.Google Scholar
  331. Snyder, S. H., Faillanie, L. A., and Weingartner, H., 1968, DOM (STP) a new hallucinogenic drug, and DOET: effects in normal subjects, Am. J. Psychiat. 125:357–364.Google Scholar
  332. Stein, L., and Wise, C. D., 1971, Possible etiology of schizophrenia: Progressive damage to the noradrenergic reward system by 6-hydroxydopamine, Science 171:1032–1036.PubMedGoogle Scholar
  333. Sugimura, T., Okabe, K., and Nagao, M., 1966, The metabolism of 4-nitroquinoline-1-oxide, a carcinogen, III. An enzyme catalyzing the conversion of 4-nitroquinoline-1-oxide to 4-hydroxyaminoquinoline-1-oxide in rat liver and hepatomas, Cancer Res. 26:1715–1721.Google Scholar
  334. Szara, S., and Axelrod, J., 1959, Hydroxylation and N-demethylation of N,N-dimethyltryptamine, Experientia 15:216–220.PubMedGoogle Scholar
  335. Tabor, C. W., Tabor, H., and Rosenthal, S. M., 1954, Purification of amine oxidase from beef plasma, J. Biol. Chem. 208:645–661.PubMedGoogle Scholar
  336. Takamizawa, A., Matsumoto, S., Iwata, T., Tochino, Y., Katagiri, K., Yamaguchi, K., and Shiratori, O., 1975, Studies on cyclophophamide metabolites and their related compounds. Preparation of an active species of cyclophosphimide and related compounds, J. Med. Chem. 18:376–383.PubMedGoogle Scholar
  337. Tansey, L. W., Estevez, V. S., and Ho, B. T., 1975, Metabolic study of 2,5-dimethoxy-4-ethylamphetamine (DOET) in rats, Proc. West. Pharmacol. Soc. 18:132.Google Scholar
  338. Taska, R. J., and Schoolar, J. C., 1972, Placental transfer and fetal distribution of mescalin-14C in monkeys, J. Pharmacol. Exp. Therap. 183:427–432.Google Scholar
  339. Taylor, K. M., and Snyder, S. H., 1970, Amphetamine: Differentiation by d and l isomers of behavior involving brain norepinephrine or dopamine, Science 168: 1487–1489.PubMedGoogle Scholar
  340. Testa, B., and Jenner, P., 1976, Drug Metabolism: Chemical and Biochemical Aspects, Marcel Dekker, New York.Google Scholar
  341. Theorell, H., 1967, Function and structure of liver alcohol dehydrogenase, Harvey Lect. 61:17–41.PubMedGoogle Scholar
  342. Thorgeirsson, S. S., Jollow, D. J., Sasame, H. A., Green, L., and Mitchell, J. R., 1973, The role of cytochrome P-450 in N-hydroxylation of 2-acetylamino fluorene, Mol. Pharmacol. 9:398–404.PubMedGoogle Scholar
  343. Tipton, K. F., Houslay, M. D., and Mantle, T. J., 1976, The nature and locations of the multiple forms of monoamine oxidase, in Monoamine Oxidase and Its Inhibition (Wolsterholme, G. E. W., and Knight, J., eds.), pp. 5–31, Elsevier-North-Holland, Amsterdam.Google Scholar
  344. Turner, D. M., 1969, The metabolism of (14C) nicotine in the cat, Biochem. J. 115:889–896.PubMedGoogle Scholar
  345. Tyler, T. R., Buhs, R. P., and Vanden Heuval, W. J. A., 1973, Identification of the mononitro derivative of dapsone as a product from an oxidation in vitro, Biochem. Pharmacol. 22:1383–1385.PubMedGoogle Scholar
  346. Ullrich, V., and Staudinger, H., 1969, Oxygen reactions in model systems, in Microsomes and Drug Oxidations (Gillette, J. R., Conney, A. H., Cosmider, G. J., Estabrook, R. W., Fouts, J. R., and Mannering, G. J., eds.), pp. 199–224, Academic Press, New York.Google Scholar
  347. Ullrich, V., and Staudinger, H., 1971, Model systems in studies of the chemistry and the enzymatic activation of oxygen, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 251–263, Springer-Verlag, Berlin.Google Scholar
  348. Uyeno, E. T., Otis, L. S., and Mitoma, C., 1968, Behavioral evaluation of hallucinagenic trimethoxyamphetamines in squirrel monkeys (Saimiri sciureus), Commun. Behav. Biol. 1:832–890.Google Scholar
  349. Vehleke, H., 1973, Mechanisms of methemoglobin formation by therapeutic and environmental agents, in Pharmacology and the Future of Man (Loomis, T. A., ed.), pp. 124–136, Karger, Basel.Google Scholar
  350. Vessell, E. S. (ed.), 1971, Drug metabolism in man, Ann. N.Y. Acad. Sci. 179.Google Scholar
  351. Vessell, E. S., Lang, C. M., White, W. J., Passananti, G. T., Hill, R. N., Clemens, T. L., Liu, D. K., and Johnson, W. D., 1976, Environmental and genetic factors affecting the response of laboratory animals to drugs, Fed. Proc. 35:1125–1132.Google Scholar
  352. Vree, T. B., Muskens, A. Th. J. M., and Van Rossom, J. M., 1972, Excretion of amphetamines in human sweat, Arch. Int. Pharmacodyn. Ther. 99:311–317.Google Scholar
  353. Walsh, M. J., Davis, V. E., and Yamanaka, Y., 1970, Tetrahydropapaveroline: An alkaloid metabolite of dopamine in vitro, J. Pharmacol. Exp. Therap. 174:388–400.Google Scholar
  354. Wang, C. U., Chiu, C. W., and Bryan, G. T., 1975, Nitroreduction of carcinogenic 5-nitrothiophenes by rat tissue, Biochem. Pharmacol. 24:1563–1568.PubMedGoogle Scholar
  355. Weber, W. W., 1971, Acetylating, deacetylating and amino acid conjugating enzymes, in Concepts in Biochemical Pharmacology, Part 2 (Brodie, B. B., and Gillette, J. R., eds.), pp. 564–583, Springer-Verlag, Berlin.Google Scholar
  356. Weinkam, R. J., Gal, J., Callery, P., and Castagnoli, N., Jr., 1976, Application of chemical ionization mass spectrometry to the study of stereoselective in vitro metabolism of 1-(3,5-dimethoxy-4-methylphenyl)-2-aminopropane, Anal. Chem. 48:203–209.PubMedGoogle Scholar
  357. Weinstein, I. B., Jeffrey, A. M., Jennette, K. W., Blobstein, S. H., Harvey, R. G., Harris, C., Autrup, H., Kasai, H., and Nakanishi, K., 1976, Benzo(a)pyrene diol epoxides as intermediates in nucleic acid binding in vitro and in vivo, Science 193:592–595.PubMedGoogle Scholar
  358. Weisburger, J. H., and Weisburger, E. K., 1973, Biochemical formation and properties of hydroxylamines and hydroxamic acids, Pharmacol. Rev. 25:1–66.PubMedGoogle Scholar
  359. Wiberg, K. B., 1955, The deuterium isotope effect, Chem. Rev. 55:713–743.Google Scholar
  360. Willi, P., and Bickel, M. H., 1973, Liver metabolic reaction: Tertiary amine N-dealkylation, teriary amine N-oxidation, N-oxide reduction, and N-oxide N-dealkylation, Arch. Biochem. Biophys. 156:772–779.PubMedGoogle Scholar
  361. Williams, R. T., 1974, Inter-species variations in the metabolism of xenobiotics, Biochem. Soc. Trans. 2:359–377.Google Scholar
  362. Williams, R. T., Caldwell, J., and Dring, L. G., 1973, Comparative metabolism of some amphetamines in various species, in Frontiers in Catecholamine Research (Usdin, E., and Snyder, S., eds.), pp. 927–932, Pergamon, New York.Google Scholar
  363. Wyatt, R. J., Erdelyi, E., DoAmaral, J. R., Elliott, G. R., Renson, J., and Barchas, J. D., 1975, Tryptoline formation by a preparation from brain with 5-methyltetrahydrofolic acid and tryptamine, Science 187:853–855.PubMedGoogle Scholar
  364. Zeller, E. A., Barsky, J., Berman, E. R., Cherkas, M. S., and Fouts, J. R., 1958, Degradations of mescaline by amine oxidases, J. Pharmacol. Exp. Therap. 124:282–289.Google Scholar
  365. Ziegler, D. M., and Mitchell, C. H., 1972, Microsomal oxidase IV. Properties of a mixed function amine oxidase isolated from pig liver microsomes, Arch. Biochem. Biophys. 150:116–125.PubMedGoogle Scholar
  366. Ziegler, D. M., McKee, E. M., and Leibman, K. C., 1973, Microsomal flavoprotein catalyzed N-oxidation of arylamines, in Microsomes and Drug Oxidations (Estabrook, R. W., Gillette, J. R., and Leibman, K. C., eds.), pp. 314–321, Williams and Wilkins, Baltimore, Maryland.Google Scholar
  367. Zweig, J. S., and Castagnoli, N., Jr., 1974, Chemical conversion of the psychotomimetic amine 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane to 5-hydroxy-2,6-dimethylindole, J. Med. Chem. 17:747–749.PubMedGoogle Scholar
  368. Zweig, J. S., and Castagnoli, N., Jr., 1975, Metabolic O-demethylation of the psychotomimetic amine l-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane, Psychopharm. Commun. 1:359–371.Google Scholar
  369. Zweig, J. S., and Castagnoli, N., Jr., 1977, In vitro metabolic O-demethylation of the psychotomimetic amine. 1-(2,5-dimethoxyl-4-methylphenyl)-2-aminopropane, J. Med. Chem. 20:414.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1978

Authors and Affiliations

  • Neal CastagnoliJr.
    • 1
  1. 1.Department of Pharmaceutical Chemistry, School of PharmacyUniversity of CaliforniaSan FranciscoUSA

Personalised recommendations