Abstract
Cytochromes P450 are the key enzymes for activating and inactivating many drugs, in particular anticancer drugs. Therefore, individual expression levels of cytochromes P450 may play a crucial role in drug safety and drug efficacy. Overexpression of cytochrome P450 may yield rapid turnover and elimination of drugs before the target site was reached and any pharmacological effect is observed. Therefore, it may be vital to know the individual cytochrome P450 status in order to select the appropriate drug before drug resistance occurs. Expression levels and activity of cytochromes P450 depend on many different factors. These factors include tissue and organ specific expression, sex- and age-dependent expression, genetic differences yielding polymorphic forms, competitive inhibition or induction of cytochromes P450 due to multiple drug interaction, nutrition and diet. Genetically engineered test cells defined for cytochromes P450 are available for studying drugs for metabolic activation and for identifying the metabolically competent cytochrome P450 isoform.
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References
Cholerton S, Daly AK, Idle JR (1992) The role of individual human cytochromes P450 in drug metabolism and clinical response. TiPS Reviews 13:434–439.
Clarke L, Waxman DJ (1989) Oxidative metabolism of cyclophosphamide: identification of the hepatic mono-oxygenase catalysts of drug activation. Cancer Res 49:2344–2350.
Doehmer J, Greim H (1993) Cytochromes P450 in genetically engineered cell cultures: the gene technological approach. In: Schenkman JB, Greim H (eds) Cytochrome P450. Heidelberg: Springer, 415–429.
Doehmer J, Seidel A, Oesch F, Glatt HR (1990) Genetically engineered V79 Chinese hamster cells metabolically activate the cytostatic drugs cyclophosphamide and ifosfamide. Env Health Persp 88:63–65.
Fuhr U, Doehmer J, Battula N, Wölfel C, Kudla C, Keita Y, Staib AH (1992) Biotransformation of caffeine and theophylline in mammalian cell lines genetically engineered for expression of single cytochrome P450 isoforms. Bioch Pharmacol 43:225–235.
Gonzalez FJ (1992) Human cytochromes P450: problems and prospects. TiPS Reviews 13:346–352.
Gonzalez FJ (1989) The molecular biology of cytochrome P450s. Pharmacological Reviews 40:243–288.
Gonzalez FJ, Crespi CL, Gelboin HV (1991) cDNA-expressed human cytochromes P450s: a new age of molecular toxicology and human risk assessment. Mutat Res 247:113–127.
Gonzalez FJ, Nebert DW (1990) Evolution of the P450 superfamiiy: animal-plant “warfare”, molecular drive and human genetic differences in drug oxidation. Trends Genet 6: 182–187.
Guengerich FP (1993) Metabolic reactions: types of reactions of cytochrome P450 enzymes. In: Schenkman JB, Greim H (eds) Cytochrome P450 Heidelberg: Springer, 89–103.
Gustafsson JA, Ingelman-Sundberg M (1975) Regulation and substrate specificity of a steroid sulfate-specific hydroxylase system in female rat liver microsomes. J Biol Chem 250: 3451–3458.
Gustafsson JA, Mode A, Norstedt G, Skett P (1983) Sex-steroid induced changes in hepatic enzymes. Annu Rev Physiol 45: 51–60.
Haim N, Nemec J, Sinha BK (1989)In vitro metabolism of etoposide (VP-16-213) by liver microsomes and irreversible binding of reactive intermediates to microsomal proteins. Biochem Pharmacol 36:527–536.
Ryan DE, Dixon R, Evans RH, Ramanathan L, Thomas PE, Wood AW, Levin W (1984) Rat hepatic cytochrome P450 isozyme specificity for the metabolism of the steroid sulfate, 5α-androstane-3α, 17β-diol-3, 17-disulfate. Arch Biochem Biophys 233:636–642.
Kimura S, Umeno M, Skoda RD, Meyer UA, Gonzalez FJ (1989) The human debrisoquine 4-hydroxylase (Cytochrome P450 2D) locus: sequence and identification of polymorphic Cytochrome P450 2D6 gene, a related gene and a pseudogene. Am J Hum Genet 45:889–905.
LeBlanc GA, Waxman DJ (1989) Interaction of anticancer drugs with hepatic mono-oxygenase enzymes. Drug Met Kev 20:395–439.
Nelson DR, Kamataki T, Waxman DJ, Guengerich FP, Estabrook RW, Feyereisen R, Gonzalez FJ, Coon MJ, Gunsalus IC, Gotoh O, Okuda K, Nebert DW (1993) The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA and Cell Biol. 12:1–51.
O'Brien PJ (1991) Molecular mechanisms of quinone cytotoxicity. Chem Biol Interactions 80:1–41.
Potter DW, Levin W, Ryan DE, Thomas PE, Reed DJ (1984) Stereoselective mono-oxygenation of carcinostatic 1-(2-chloropethyl)-3-(cyclohexyl)-1-nitrosourea by purfied cytochrome P450 isoenzymes. Biochem Pharmacol 33: 609–613.
Prough RA, Brown MI, Dannan GA, Guengerich FP (1984) Major isozymes of rat liver microsomal cytochrome P450 involved in the N-oxidation of N-isopropyl-a-(2-methylazo)-p-toluamide, the azo derivative of procarbazine. Cancer Res 44:543–548.
Powis G (1989) Free radical formation by antitumor quinones. Free Rad Biol Med 6:63–101.
Powis G (1987) Metabolism and reactions of quinoid anticancer agents. Pharmac Ther 35:57.
Rogiers V, Vandenberghe Y, Callaerts A, Verleye G, Cornet M, Mertens K, Sonck W, Vercruysse A (1990) Phase I and phase II xenobiotic biotransformation in cultures and cocultures of adult rat hepatocytes. Biochem Pharmacol 40: 1701–1706.
Ryan DE, Levin W (1993) Age- and gender-related expression of rat liver cytochrome P450. In: Schenkman JB, Greim H (eds) Cytochrome P450. Heidelberg: Springer, 461–476.
Slater TF, Sawyer BC (1971) The stimulatory effects of carbon tetrachloride on peroxidative reactions in rat liver fractionin vitro. Biochem J 123:815–821.
Waxman DJ, Dannan GA, Guengerich FP (1985) Regulation of rat hepatic cytochrome P450: age-dependent expression, hormonal imprinting, and exnobiotic inducibility of sexspecific isoenzymes. Biochemistry 24:4409–4417.
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Doehmer, J., Goeptar, A.R. & Vermeulen, N.P.E. Cytochromes P450 and drug resistance. Cytotechnology 12, 357–366 (1993). https://doi.org/10.1007/BF00744673
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DOI: https://doi.org/10.1007/BF00744673