Abstract
A variety of enzyme systems are capable of accepting structurally diverse, lipid-soluble compounds as substrates. The reactions they catalyze generally lead to more water-soluble products that are excreted more rapidly than the parent compounds. These metabolic pathways often control the rate of elimination of a number of drugs (Testa & Jenner, 1976). The generality of these pathways of metabolism for a large number of drugs and the capacity of these enzymes to metabolize a variety of structurally diverse compounds distinguishes them as drugmetabolizing enzymes. Enzymes that include a limited spectrum of drugs among their substrates are generally not distinguished in this manner.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
ARIAS, I.M. (1961). Etheral and N-linked glucuronide formation by normal and Gunn rats in vitro and in vivo. Biochem. biophys. Res. Commun., 6, 81–84.
ATLAS, S.A., BOOBIS, A.R., FELTON, J.S., THORGEIRSSON, S.S. & NEBERT, D.W. (1977). Ontogenetic expression of polycyclic aromatic compound-inducible monooxygenase activities and forms of cytochrome P-450 in rabbit. J. biol. Chem., 252, 4712–4721.
ATLAS, S., THORGEIRSSON, S., BOOBIS, A., KUMAKI, K. & NEBERT, D. (1975). Differential induction of murine Ah locus-associated with monooxygenase activities in rabbit liver and kidney. Biochem. Pharmac., 24, 2111–2116.
DIETER, H.H. & JOHNSON, E.F. (1982). Functional and structural polymorphism of rabbit microsomal cytochrome P-450 form 3b. J. biol. Chem., 257, 9315–9323.
FUJII-KURIYAMA, Y., MIZUKAMI, Y., KAWAJIRI, K., SOGAWA, K. & MURAMATSU, M. (1982). Primary structure of cytochrome P-450: Coding nucleotide sequence of phenobarbital-inducible cytochrome P-450 cDNA from rat liver. Proc. natn. Acad. Sci. U.S.A., 79, 2793–2797.
GILLETTE, J.R., DAVIS, D.C. & SASAME, H.A. (1972). Cytochrome P-450 and its role in drug metabolism A. Rev. Pharmac., 12, 57–84.
JOHNSON, E.F. (1979). Multiple forms of cytochrome P-450: Criteria and Significance. Rev. Biochem. Toxicol., 1, 1–26.
JOHNSON, E.F., DIETER, H.H., SCHWAB, G.E., REUBI, I. & MULLER-EBERHARD, U. (1982). Rabbit microsomal cytochrome P-4501: A cytochrome linked to variations in hepatic steroid hormone metabolism. In Cytochrome P450: Biochemistry, Biophysics, and Environmental Implications. Hanninen, O. (ed.) pp. 283–290, Amsterdam: Elsevier/North Holland Biomedical Press.
JOHNSON, E.F., LEVITT, D.S., MULLER-EBERHARD, U. & THORGEIRSSON, S.S. (1980). Catalysis of divergent pathways of 2-acetylaminofluorene metabolism by muliqb b forms of cytochrome P-450. Cancer Res., 40, 4456–4459.
JOHNSON, E.F. & MULLER-EBERHARD, U. (1977a). Resolution of two forms of cytochrome P450 from liver microsomes of rabbits treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. biol. Chem., 252, 2839–2845.
JOHNSON, E.F. & MULLER-EBERHARD, U. (1977b). Multiple forms of cytochrome P-450: Resolution and purification of rabbit liver aryl hydrocarbon hydroxylase. Biochem. biophys. Res. Commun., 76, 644–651.
JOHNSON, E.F. & SCHWAB, G.E. (1984). Constitutive forms of rabbit liver microsomal cytochrome P-450: Enzymatic diversity, polymorphism and allosteric regulation. Xenobiotica, 14, 2–18.
JOHNSON, E.F., SCHWAB, G.E. & MULLER-EBERHARD, U. (1979). Multiple forms of cytochrome P-450: Catalytic differences exhibited by two homogeneous forms of rabbit cytochrome P-450. Mol. Pharmac., 15, 708–717.
KOOP, D., MORGAN, E., TARR, G. & COON, M. (1982). Purification and characterization of a unique isozyme of cytochrome P-450 from liver microsomes of ethanoltreated rabbits. J. biol. Chem., 257, 8472–8480.
KUMAR, A., RAPHAEL, C. & ADESNIK, M. (1983). Cloned cytochrome P-450 cDNA: Nucleotide sequence and homology to multiple phenobarbital induced mRNA species. J. biol. Chem., 258, 11280–11284.
LANGE, R., BALNY, C. & MAUREL, P. (1984). Inductive and repressive effects of rifampicin on rabbit liver microsomal cytochrome P-450. Biochem. Pharmac. (in press).
DHTON EL, J.K., DEBRUNNER-VOSSBRINCK, B.A. & KEMPER, B. (1984). Isolation and sequence analysis of three cloned cDNAs for rabbit liver proteins that are related to rabbit cytochrome P-450 (Form 2), the major phenobarbital-inducible form. Biochemistry, 23, 204–210.
LIEM, H.H., MULLER-EBERHARD, U. & JOHNSON, E.F. (1980). Differential induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin of multiple forms of rabbit microsomal cytochrome P-450: Evidence for tissue specificity. Mol. Pharmac., 18, 565–570.
LU, A.Y.H. & WEST, S.B. (1980). Multiplicity of mammalian microsomal cytochromes P-450. Pharmac. Rev., 31, 277–295.
MILLER, E.C. & MILLER, J.A. (1974). In The Molecular Biology of Cancer, Busch, H. (ed.) pp. 377–402, New York: Academic Press.
MILSTEIN, C. (1980). Monoclonal Antibodies. Sci. Am., 243, 66–74.
NEBERT, D.W., EISEN, H.J., NEGISHI, M., LANG, M.A., HJELMELAND, L.M. & OKEY, A.B. (1981). Genetic mechanisms controlling the induction of polysubstrate monooxygenase (P-450) activities. A. Rev. Pharmac. Toxicol., 21, 431–462.
NEGISHI, M. & NEBERT, D.W. (1981). Structural gene products of the Ah complex. Increases in large mRNA from mouse liver associated P-450 induction by 3-methylcholanthrene. J. biol. Chem., 256, 3085–3091.
NORMAN, R.L., JOHNSON, E.F. & MULLER-EBERHARD, U. (1978). Identification of the major cytochrome P-450 form transplacentally induced in neonatal rabbits by 2,3,7,8-tetrachlorodibenzo-p-dioxin. J. biol. Chem., 252, 8640–8647.
REUBI, I., GRIFFIN, K.J., RAUCY, J.L. & JOHNSON, E.F. (1984a). Three monoclonal antibodies to rabbit microsomal cytochrome P-450 1 recognize distinct epitopes that are shared to different degrees among other electrophoretic types of cytochrome P-450. J. biol. Chem., 259, 5887–5892.
REUBI, I., GRIFFIN, K.J., RAUCY, J. & JOHNSON, E.F. (1984b). Use of a monoclonal antibody specific for rabbit monoclonal cytochrome 3b to characterize the participation of this cytochrome in the microsomal 6β-and 16α-hydroxylation of progesterone. Biochemistry (in press).
RITCHIE, J.C., SLOAN, T.P., IDLE, J.R. & SMITH, R.L. (1980). Toxicological implications of polymorphic drug metabolism. Ciba Foundation Symposium, 76, pp. 219–244.
ROBERTSON, I.G.C., SERABJIT-SINGH„ C., CROFT, J.E. & PHILPOT, R.M. (1983). The relationship between increases in the hepatic content of cytochrome P-450, form 5, and in the metabolism of aromatic amines to mutagenic products following treatment of rabbits with phenobarbital. Mol. Pharmac., 24, 1–5.
TESTA, B. & JENNER, P. (1976). Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker.
TUKEY, R.H., OKINO, S., BARNES, H.S., GRIFFIN, K.J. & JOHNSON, E.F. (1984). Direct immunological detection of cDNA clones encoding rabbit P-450 6 and the identification of related cDNA clones. Fedn Proc., 43, 2034.
VIEIRA, J. & MESSING, J. (1982). The pUC plasmids an M13mp7-derived system for inserting mutagenesis and sequencing with synthetic universal primers. Gene, 19, 259–268.
WATSON, J.D., TOOZE, J. & KURTZ, D.T. (1983). Recombinant DNA: A Short Course. New York: W.H. Freeman & Co.
WHITE, P., NEW, M. & DUPONT, B. (1984). Cloning and expression of cDNA clones encoding a bovine adrenal cytochrome P-450 specific for steroid 21-hydroxylation. Proc. natn. Acad. Sci. U.S.A., 81, 1986–1990.
WOOD, A.W. (1979). Genetic regulation of coumarin hydroxylase activity in mice. J. biol. Chem., 254, 5641–5646.
Author information
Authors and Affiliations
Editor information
Copyright information
© 1984 Macmillan Publishers Limited
About this chapter
Cite this chapter
Johnson, E.F., Finlayson, M.J., Raucy, J., Tukey, R.H. (1984). Characterization of the multiplicity of drug-metabolizing enzymes: observations on cytochrome P-450 diversity. In: Paton, W., Mitchell, J., Turner, P., Padgham, C., Ashcroft, E. (eds) IUPHAR 9th International Congress of Pharmacology London 1984. Palgrave Macmillan, London. https://doi.org/10.1007/978-1-349-17615-1_29
Download citation
DOI: https://doi.org/10.1007/978-1-349-17615-1_29
Publisher Name: Palgrave Macmillan, London
Print ISBN: 978-0-333-37136-7
Online ISBN: 978-1-349-17615-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)