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Stereoselective Bioactivation and Bioinactivation — Toxicological Aspects

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Stereochemical Aspects of Drug Action and Disposition

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 153))

Abstract

Stereoisomerism manifests itself in various forms, such as those related to enantiomers, diastereoisomers, epimers, meso- and geometrical isomers. Generally speaking, the consequences of stereoisomerism for the biological action of xenobiotics in living organisms are still difficult to predict because they are complex and of multi-factorial origin. In recent years, however, significant progress has been made in rationalization and understanding of toxicity at the molecular level. In the development of a toxic effect, nowadays the following stages are usually distinguished: (a) toxicokinetics (i.e., comprising absorption, distribution, and elimination); (b) biotransformation, either resulting in bioactivation or bioinactivation; (c) reversible or irreversible interactions with cellular or tissue components; (d) protection or repair mechanisms; and (e) the nature and extent of the toxic effect for the organism. By taking these stages into consideration and by realizing the intrinsic asymmetry of receptors, enzymes, and other types of macromolecules, which leads to the phenomenon of “chiral recognition,” rationalization of stereoselectivity in toxicity becomes more and more feasible.

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References

  • Armstrong RN, Andre JC, Bessems JGM (1988) Mechanistic and stereochemical investigations of UDP-glucuronosyltransferases. In: Siest G, Magdalou J, Burchell B (eds) Cellular and Molecular Aspects of Glucuronidation Colloque. Inserm. John Libbey Eurotext Ltd., London, 173:51–58

    Google Scholar 

  • Akira K, Taira T, Hasegawa H, Sakuma C, Shinehara Y (1998) Studies on the stereoselective internal acyl migration of ketoprofen glucuronides. Drug Metab Disp 26:457-164

    Google Scholar 

  • Baertschi SW, Raney KD, Shimada T, Harris TM, Guengerich FP (1989) Comparison of rates of enzymatic oxidation of anatoxin Bl, anatoxin Gl, and sterigmatocystin and activities of the epoxides in forming guanyl-N7 adducts and inducing different genetic responses. Chem Res Toxicol 2:114–122

    Article  PubMed  CAS  Google Scholar 

  • Baillie TA, Schultz (1997) Stereochemistry in drug development; role of chirality as a determinant of drug action, metabolism and toxicity. In: Aboul-Enein HY, Wainer IW (eds) The impact of stereochemistry on drug development and use. John Whiley&Sons, New York, pp 21–42

    Google Scholar 

  • Bajpai M, Roskos LK, Shen DD, Levy RH (1996) Roles of cytochrome P450 2C9 and 2C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Disp 24:1401–1403

    CAS  Google Scholar 

  • Benz CC, Kenry MA, Ford JA, Townsend AJ, Cox FW, Palayoor S, Matlin SA, Hait WN, Cowan KH (1990) Biochemical correlates of the antitumor and antimitochondrial properties of gossypol enantiomers. Mol Pharmacol 37:840–848

    PubMed  CAS  Google Scholar 

  • Blaschke G, Graute WF (1987) Enantiomere des Konfigurationsstabilen C-Methyl-thalidomids. Liebigs Ann Chem 647–648

    Google Scholar 

  • Boobis AR, Murray S, Hampden CE, Davies DS (1985) Genetic polymorphism in drug oxidation: in vitro studies of human debrisoquine 4-hydroxylase and bufuralol 1’hydroxylase activities. Biochem Pharmacol 34:65–71

    Article  PubMed  CAS  Google Scholar 

  • Caldwell (1999) Through the looking glass in chiral drug development. Modern Drug Discovery 51–60

    Google Scholar 

  • Commandeur JNM, Vermeulen NPE (1990) Molecular and biochemical mechanisms of chemically-induced nephrotoxicity: a review. Chem Res Toxicol 3:171–194

    Article  PubMed  CAS  Google Scholar 

  • Commandeur JNM, Stijntjes GJ, Wijngaard J, Vermeulen NPE (1991) Metabolism of L-cysteine S-conjugates and N-(trideuteroacetyl)-L-cysteine S-conjugates of four fluoroethylenes in the rat. Role of balance of deacetylation and acetylation in relation to the nephrotoxicity of mercapturic acids. Biochem. Pharmacol 42:31–38

    Article  PubMed  CAS  Google Scholar 

  • Commandeur JNM, Stijntjes GJ, Vermeulen NPE (1995) Enzymes and transport systems involved in the formation and disposition of glutathione S-conjugates. Role in bioactivation and detoxication mechanisms of xenobiotics. Pharmacol Rev 47:271–330

    PubMed  CAS  Google Scholar 

  • Cox PJ, Farmer PB, Jarman M, Jones J, Stec WJ, Kinas R (1976) Observations on the differential metabolism and biological activity of the optical isomers of cyclophosphamide. Biochem Pharmacol 25:993–999

    Article  PubMed  CAS  Google Scholar 

  • De Groot MJ, Vermeulen NPE, Kramer JD, Van Acker FAA, Donné-Op den Kelder GM (1996) A three-dimensional protein model for human cytochrome P450 2D6 based on the crystal structures of P450 101, P450 102 and P450 108. Chem Res Tox 9:1079–1091

    Article  Google Scholar 

  • De Groot MJ, Bijloo GJ, Martens BJ, Van Acker FAA, Vermeulen NPE (1997) A refined substrate model for human Cytochrome P450 2D6. Chem Res Toxicol 10:41–48

    Article  PubMed  Google Scholar 

  • De Groot MJ, Ackland MJ, Home VA, Alex AA, Jones BC (1999) A novel approach to predicting P450 mediated drug metabolism. CYP 2D6 calatyzed TV-dealkylation reactions an qualitative metabolite predictions using a combined protein and pharmacophore model for CYP 2D6. J Med Chem 42:4062–4070

    Article  PubMed  Google Scholar 

  • Devanesan PD, Cremonesi P, Nunnally JE, Rogan EG, Cavalieri EL (1990) Metabolism and mutagenicity of dibenzo[a,e]pyrene and the very potent environmental carcinogen dibenzo[a,e]pyrene. Chem Res Toxicol 3:580–586

    Article  PubMed  CAS  Google Scholar 

  • Distlerath LM, Reilly PEB, Martin MV, Wilkinson GR, Guengerich FP (1985) Immunochemical characterization of the human liver cytochrome P450 involved in debrisoquine hydroxylation. In: Boobis AR, Caldwell J, De Matters F, Elcombe CR (eds) Microsomes and Drug Oxidations. Taylor&Francis, London, pp 380–389

    Google Scholar 

  • Ebner T, Meese CO, Eichelbaum M (1995) Mechanism of Cytochrome P450 2D6-catalyzed sparteine metabolism. Molec. Pharmacol 48:1078–1086

    CAS  Google Scholar 

  • Eriksson T, Björkman S, Roth B, Fyge A, Hoglund P (1995) Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 7:44–52

    Article  PubMed  CAS  Google Scholar 

  • Gallo MA, Ill HCP, Dragan YP, Anthony DC, Montine TJ, Graham DG, Rüssel FE, Norton S (1996) In: Casarett and Doull’s Toxicology—The Basic Science of Poisons. McGraw-Hill, New York, chapters 1, 8, 26 and 27

    Google Scholar 

  • Goetz CG, Meisel E (2000) Biological Neurotoxins. Neurol Clin 18:719–740

    Article  PubMed  CAS  Google Scholar 

  • Granvil CP, Madan A, Sharkawi M, Parkinson A, Wainer IW (1999) Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes. Drug Metab Dispos 27:533–541

    PubMed  CAS  Google Scholar 

  • Guengerich FP (1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P450 enzymes. Chem Res Toxicol 4:391–407

    Article  PubMed  CAS  Google Scholar 

  • Guengerich FP, Johnson WW (1999) Kinetics of hydrolysis and reaction of anatoxin B1exo-8,9-epoxide and relevance to toxicity and detoxication. Drug Metab Rev 31:141–158

    Article  PubMed  CAS  Google Scholar 

  • Hagen M, Pabel U, Landsiedel R, Bartsch I, Falany CN, Glatt HR (1998) Expression of human estrogen sulfotransferase in S-typhimurium: differences between hHST and hEST in the enantioselective activation of 1-hydroxyethylpyrene to a mutagen. Chem Res Interact 109:249–253

    Article  CAS  Google Scholar 

  • Hayball PJ (1995) Formation and reactivity of acyl-glucuronides. The influence of chirality. Chirality 7:1–9

    CAS  Google Scholar 

  • Iyer R, Coles B, Raney KD, Their R, Guengerich FP, Harris TM (1994) Title follows. J Amer Chem Soc 116:1603–1619

    Article  CAS  Google Scholar 

  • Jerina DM, Sayer JM, Yagi H, Van Bladeren PJ, Thakker DR, Levin W, Chang RL, WoodT AW, Conney AH (1985) In: Boobis AR, Caldwell J, De Mattheis F, Elcombe R (eds) Microsomes and Drug Oxidations. Taylor&Francis, London, pp 310–319

    Google Scholar 

  • Joseph AEA, Matlin SA, Knox P (1986) Cytotoxicity of enantiomers of gossypol. Brit J Cancer 54:511–518

    Article  PubMed  CAS  Google Scholar 

  • Kaminsky LS, Dunbar DA, Wang PP, Beaune P, Larrey D, Guengerich FP, Schnellmann RG, Sipes IG (1984) Human hepatic cytochrome P450 composition as probed by in vitro microsomal metabolism of warfarine. Drug Metab Dispos 12:470–476

    PubMed  CAS  Google Scholar 

  • Kling J (2000) Redeeming thalidomide: clinical trials for this notorious drug suggest uses against cancer and autoimmune diseases. Mod Drug Discov, p 35

    Google Scholar 

  • Koymans LMH, Vermeulen NPE, van Acker SABE, te Koppele JM, Heykants JJP, Lavrijsen K, Meuldermans W, Donné-Opdenkelder GM (1992) A predictive model for substrates of cytochrome P450-debrisoquine (2D6) Chem Res Toxicol 5:211–219

    Article  PubMed  CAS  Google Scholar 

  • Landsiedel R, Pabel U, Engst W, Ploske J, Seidel A, Glatt HR (1998) Chiral inversion of 1-hydroxyethylpyrene enantiomers mediated by enantioselective sulfo transferases. Biochem Biophys Res Comm 247:181–185

    Article  PubMed  CAS  Google Scholar 

  • Lightfoot T, Ellis SW, Mahling J, Acklands MJ, Blaney FE, Bijloo GJ, de Groot MJ, Vermeulen NPE, Blackburn GM, Lennard MS, Tucker GT (2000) Regioselective hydroxylation of debrisoquine by cytochrome P450 2D6: implications for active site modelling. Xenobiotica 30:219–233

    Article  PubMed  CAS  Google Scholar 

  • Lin LY, DiStefano EW, Schmitz DA, Hsu L, Ellis SW, Lennard MS, Tucker GT, Ch AK (1997) Oxidation of methamphetamine and methylenedioxymethamphetamine by Cyp 2D6. Drug Metab Disp 25:1059–1064

    CAS  Google Scholar 

  • Madyastha KM, Gaikwad NW (1998) Metabolic fate of S-(-)-pulegone in rat. Xenobiotica 28:723–734

    Article  PubMed  CAS  Google Scholar 

  • Mason JP and Hut AJ (1997) Stereochemical aspects of drug metabolism (1997) In: Aboul-Enein HY, Wainer IW (eds) The impact of stereochemistry on drug development and use. John Whiley&Sons, New York, pp 45–106

    Google Scholar 

  • Meese CO, Fisher C, Eichelbaum M (1988) Stereoselectivity of the 4-hydroxylation of debrisoquine in man, detected by GC-MS. Biomed Environ Mass Spectrom 15:63–71

    Article  PubMed  CAS  Google Scholar 

  • Meyer UA, Gut J, Kronback T, Scoda C, Meier UT, Catin T, Dayer P (1986) The molecular mechanism of two common polymorphisms of drug oxidation—evidence for functional changes in cytochrome P450 isoenzymes catalyzing bufuralol and mephenytoin oxidation. Xenobiotica 16:449–464

    Article  PubMed  CAS  Google Scholar 

  • Mulder GJ, Coughtrie MWH, Burchell B (1990) Glucuronidation, In: Mulder GJ (ed.) Conjugation Reactions in Drug Metabolism: An Integrated Approach Taylor & Francis, London, pp 51–107

    Google Scholar 

  • Nelson SD (1995) Mechanisms of the formation and disposition of reactive metabolites that can cause acute liver injury. Drug Metab Rev 27:147–177

    Article  PubMed  CAS  Google Scholar 

  • Ockzenfelz H, Köhler E, Meise W (1976) Teratogene Wirkung und Stereospezifität eines Thalidomid-Metaboliten. Pharmazie 31:492–493

    Google Scholar 

  • Raney KD, Meyer DJ, Ketterer B, Harris TM, Guengerich FP, (1992) Glutathione conjugation of anatoxin Bl exo- and endoepoxides by rat and human glutathione S- transferases. Chem Res Toxicol 5:470–478

    Article  PubMed  CAS  Google Scholar 

  • Reist M, Carrupt P-A, Francotte E, Testa B (1998) Chiral inversion and hydrolysis of thalidomide: mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites. Chem Res Toxicol 11:1521–1528

    Article  PubMed  CAS  Google Scholar 

  • Relling MV, Ayoma T, Gonsales FJ, Meyer UA (1990) Tolbutamide and mephenytoin hydroxylation by human cytochrome P450 s in the CYP2Cu subfamily. J Pharmacol Exp Ther 252:442–447

    PubMed  CAS  Google Scholar 

  • Riddle JM and Estes JW (1992) Oral contraceptives in ancient and medieval times. Amer Sei 80:226–233

    Google Scholar 

  • Rojas M, Alexandrov K, (1986) In vivo formation and persistence of DNA adducts in mouse and rat skin exposed to benzo[a]pyrene-dihydrodiols and-dihydrodiolepoxides. Carcinogenesis 7:1553–1556

    Article  PubMed  CAS  Google Scholar 

  • Screnci D, Hambley TW, Galettis P, Brouwer W, McKeage MJ (1997) Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin. Br J Cancer 76:502–510

    Article  PubMed  CAS  Google Scholar 

  • Seidel A, Friedberg F, Löllmann B, Schwierzoek A, Funk M, Frank H, Holler Romy, Oesh F, Glatt HR (1998) Detoxication of optically active bay region polycyclic aromatic hydrocarbon dihydrodiol epoxides by human GST Pl-1 expressed in Chinese hamster V79 cells. Carcinogenesis 19:1975–1981

    Article  PubMed  CAS  Google Scholar 

  • Singh G, Koropatnick J (1988) Differential toxicity of eis and trans isomers of dichlorodiammineplatinum. J Biochem Toxicol 3:223–233

    Article  PubMed  CAS  Google Scholar 

  • Ter Laak AM, Vermeulen NPE (2001) Molecular modeling approaches to predict metabolism and toxicity. In: Testa B, Waterbeemd H vd, Folkers G, Guy R (eds) The Second logP Symposium Lipophilicity in Drug Disposition, Verlag Helvetica, Chimica Acta, Zürich

    Google Scholar 

  • Thulasiram HV, Gada AK, Madyastha MK (2000) Role of C-5 chiral center in R-(+)- pulegone-mediated hepatotoxicity: metabolic disposition and toxicity of 5,5-dimethyl-2-(l-methylethylidene)-cyclohexagone in rats. Drug Metab Disp 28:833–844

    CAS  Google Scholar 

  • Thijssen HHW and Baars LGM (1987) The biliary excretion of acenocoumarol in the rat: stereochemical aspects. J Pharm Pharmacol 39:655–657

    Article  PubMed  CAS  Google Scholar 

  • Vermeulen NPE, Te Koppele JM (1993) Stereoselective biotransformation. Toxicological consequences and implications. In: Wainer IW (ed.) Drug Stereochemistry (2nd edition, revised and expanded), Marcel Dekker, Inc., New York/Basel/Hong Kong, pp 245–280

    Google Scholar 

  • Walle T, Walle UK, (1990) Stereoselective sulphate conjugation of racemic terbutaline by human liver cytosol. Brit J Clin Pharmacol 30:127–133

    Article  CAS  Google Scholar 

  • Williams KM (1990) Enantiomers in arthritic disorders. Pharmacol. Ther 46:273–295

    Article  PubMed  CAS  Google Scholar 

  • Williams ML, Wainer IW, Granvil CL, Bernstein ML, Ducharme MP (1999a) Pharmacokinetics of (R)- and (S)-cyclophosphamide and their dechloroethylated metabolites in cancer patients. Chirality 11:301–308

    Article  PubMed  CAS  Google Scholar 

  • Williams ML, Wainer IW (1999c) Cyclophosphamide versus ifosfamide: to use ifosfamide or not to us, that is the three-dimensional question. Curr Pharm Des 5:665–672

    PubMed  CAS  Google Scholar 

  • Williams ML, Wainer IW, Embree L, Barnett M, Granvil CL, Ducharme MP (1999b) Enantioselective induction of cyclophosphamide metabolism by phenytoin. Chirality 11:569–574

    Article  PubMed  CAS  Google Scholar 

  • Wood AW, Chang RL, Kumar S, Shirai N, Jerina DM, Lehr RE, Conney AH (1986) Bacterial and mammalian cell mutagenicity of four optically active bay-region 3,4-Diol-l,2-epoxides and other derivatives of the nitrogen heterocycle dibenz[c,h] acridine. Cancer Res 46:2760–2766

    PubMed  CAS  Google Scholar 

  • Wormhoudt LW, Commandeur JNM, Vermeulen NPE (1999) Genetic polymorphisms of human TV-acetyltransferase, Cytochrome P450, Glutathione 5-Transferase and epoxide hydrolase enzymes—Relevance to Xenobiotic Metabolism and Toxicity. Crit Rev Toxicol 29:59–124

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. N. P. E. Vermeulen
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Editors and Affiliations

  1. Institut für Klinische Pharmakologie, Dr. Margarete-Fischer-Bosch, Auerbachstr. 112, 70376, Stuttgart, Germany

    Michel Eichelbaum

  2. School of Pharmacy, University of Lausanne School of Pharmacy, 1015, Lausanne, Switzerland

    Bernard Testa

  3. Dept. of Clinical and Experimental Pharmacology, University of Adelaide, 5005, Adelaide, Australia

    Andrew Somogyi

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Vermeulen, N.P.E. (2003). Stereoselective Bioactivation and Bioinactivation — Toxicological Aspects. In: Eichelbaum, M., Testa, B., Somogyi, A. (eds) Stereochemical Aspects of Drug Action and Disposition. Handbook of Experimental Pharmacology, vol 153. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55842-9_10

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  • DOI: https://doi.org/10.1007/978-3-642-55842-9_10

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-62575-6

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