Structural Models for Substrates and Inhibitors of Cytochrome P450 Enzymes
Although a large number of drugs, chemicals, and endogenous compounds are known as substrates or inhibitors of microsomal cytochrome P450 enzymes, systematic attempts to explore substrate and inhibitor specificity of individual cytochrome P450 species have been occasional. An improved understanding of the specificity of individual cytochrome P450 enzymes, however, is desirable for several reasons. First, animal species differ from each other and from humans with respect to their patterns of cytochrome P450 enzymes involved in detoxication and bioactivation of cytotoxic and genotoxic chemicals. More knowledge of the specificity of these enzymes facilitates the explanation of species differences in metabolism and facilitates the design of chemical toxicity studies. Furthermore, reliable substrate models offer the opportunity to predict whether a drug is likely to be a substrate of a particular cytochrome P450 enzyme and thus whether its plasma concentration and, consequently, its therapeutic effects may be subjected to interindividual variations of the activity of this enzyme. Likewise, more knowledge about structural features of compounds inhibitory for cytochrome P450 enzymes is required, to evaluate whether one drug may be inhibitory for the metabolism of one or more other drugs.
KeywordsPolycyclic Aromatic Hydrocarbon Pyrene Aniline Metoprolol Anthracene
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- Hansch C (1971) Quantitative structure-activity relationships in drug design. In: Ariens EJ (ed) Drug design, vol 1. Academic, New York, pp 271–342Google Scholar
- Jerina DM, Michaud DP, Feldmann RJ, Armstrong RN, Vyas KP, Thakker DR, Yagi H, Thomas PE, Ryan DE, Levin W (1982) Stereochemical modeling of the catalytic site of cytochrome P-450c. In: Sato R, Kato R (eds) Microsomes, drug oxidations, and drug toxicity. Japan Scientific Societies, Tokyo, pp 195–201Google Scholar
- Kronbach T, Dayer P, Meyer UA (1985) Debrisoquine(D)/sparteine (SP)-type polymorphism in drug oxidation: a model of the active site of the involved cytochrome P-450 isozyme. Experientia 41: 822Google Scholar
- Kronbach T, Mathys D, Gut J, Catin T, Meyer UA (1987) High performance liquid chromatographic assays for bufuralol l’-hydroxylase, debrisoquine 4- hydroxylase, and dextromethorphan O-demethylase in microsomes and purified cytochrome P450 isozymes of human liver. Anal Biochem 162: 24–32PubMedCrossRefGoogle Scholar
- Laughton CA, Neidle S (1990) Inhibitors of the P-450 enzymes aromatase and lyase. Crystallographic and molecular modeling studies suggest structural features of pyridylacetic acid derivatives responsible for differences in enzyme inhibitory activity. J Med Chem 33: 3055–3060PubMedCrossRefGoogle Scholar
- Lu AYH, West SB (1980) Multiplicity of mammalian microsomal cytochromes P-450. Pharmacol Rev 31: 277–295Google Scholar
- Strobl GR, Wolff T (1992a) Structural models for inhibitors and substrates of cytochrome P-450 2D6 based on molecular modeling analysis. In: Archakov AI, Bachmanova (eds) Cytochrome P-450: structure and function, biotechnological and ecological aspects. INCO-TNC, Moscow, Russia, 1992, pp 736–738Google Scholar
- Strobl GR, von Kruedener S, Stoeckigt J, Guengerich FP, Wolff T (1992b) Development of a pharmacophor for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies. J Med Chem 1993 (in press)Google Scholar
- Tullman RH, Walsh JS, Miwa GT (1984) The stereochemistry of P-450 and P-448 catalyzed O-dealkylation of 7-ethoxycoumarin. Fed Proc 43: 346Google Scholar
- Verloop A, Hoogenstraaten W, Tipker J (1976) Development and applications of new steric substituent parameters in drug design. In: Ariens EJ (ed) Drug design, vol 7. Academic, New York, pp 165–207Google Scholar
- Wolff T, Distlerath LM, Worthington MT, Groopman JD, Hammons GJ, Kadlubar FF, Prough RA, Martin MV, Guengerich FP (1985) Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling. Cancer Res 45: 2116–2122PubMedGoogle Scholar