The 1990 Pharmaceutical Manufacturers Association of Canada Keynote Lecture. The role of the cytochromes P450 in the detoxication and activation of drugs and other chemicals
The roles of the cytochromes P450 are reviewed, with emphasis on their involvement in the detoxication of drugs and chemicals, the activation of carcinogens, and the toxicity of drugs. Cytochromes P450 have different characteristics. P450I mostly activates carcinogens and other chemicals by forming oxygenated reactive intermediates, which are also associated with the formation of neoantigens and immunotoxicity. P450IIE has a propensity to form oxygen radicals, which are cytotoxic and carcinogenic; other cytochromes generate oxygen radicals by futile cycling when activated by difficultly metabolized substrates. Novel procedures for the safety evaluation of chemicals are described; COMPACT is based on the computer graphic determination of the spatial conformation and electronic structure of chemicals to enable their activating cytochromes P450, and hence their toxicity, to be established; ENACT is based on quantifying the induction of individual cytochromes P450, since the extent of induction of P450I, and possibly other activating cytochromes, is directly related to the carcinogenic potential of the chemical.Key words: cytochromes P450, oxygen radicals, enzyme induction, drug metabolism, chemical toxicity.