Metabolic activation of carcinogens and toxic chemicals.
1. The spatial parameters and electronic structures of 100 exogenous and endogenous chemicals have been determined by computer graphics, from which their oxidative metabolism by the cytochrome P-448 (activation) or the other families of cytochromes P-450 (generally detoxication) have been predicted. 2. The spatial parameters of these chemicals primarily determine the family of cytochrome P-450 by which the chemicals are metabolized and the electronic structures primarily determine their ease of oxidative metabolism. 3. The role of oxidative metabolism of xenobiotics by the cytochromes P-448, and their binding to the cytosolic Ah receptor, are considered in relationship to the mechanisms of chemical toxicity, mutagenicity, carcinogenicity, and co-carcinogenicity. 4. The mechanisms of chemical toxicity and carcinogenesis are considered in respect of activation through cytochrome P-448-mediated, conformationally-hindered oxygenation to reactive intermediates which, unlike most cytochrome P-450-oxygenated metabolites, are not acceptable substrates for conjugation and detoxication and therefore react with essential intracellular macromolecules. 5. The computer graphic method of determining the molecular conformations and electronic structures of molecules is a rapid, scientifically-based procedure for evaluation of the potential toxicity, mutagenicity and carcinogenicity of chemicals.
Parke
D V
DV
Department of Biochemistry, University of Surrey, Guildford, UK.
Ioannides
C
C
Lewis
D F
DF
D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D003196:Computer Graphics; D019388:Cytochrome P-450 CYP1A2; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003580:Cytochromes / Q000378:metabolism*; D006801:Humans; D015394:Molecular Structure; D009153:Mutagens; D015262:Xenobiotics / Q000493:pharmacokinetics*
D002273:Carcinogens; D003580:Cytochromes; D009153:Mutagens; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; C017170:Cyp1a2 protein, rat; D019388:Cytochrome P-450 CYP1A2