Cytochromes P450 in the bioactivation of chemicals.
The initial view that the cytochrome P450 enzyme system functions simply in the deactivation of xenobiotics is anachronistic on the face of mounting evidence that this system can also transform many innocuous chemicals to toxic products. However, not all xenobiotic-metabolising cytochrome P450 subfamilies show the same propensity in the bioactivation of chemicals. For example, the CYP2C, 2B and 2D subfamilies play virtually no role in the bioactivation of toxic and carcinogenic chemicals, whereas the CYP1A, 1B and 2E subfamilies are responsible for the bioactivation of the majority of xenobiotics. Electronic and molecular structural features of organic chemicals appear to predispose them to either bioactivation by one cytochrome P450 enzyme or deactivation by another. Consequently, the fate of a chemical in the body is largely dependent on the cytochrome P450 profile at the time of exposure. Any factor that modulates the enzymes involved in the metabolism of a certain chemical will also influence its toxicity and carcinogenicity. For example, many chemical carcinogens bioactivated by CYP1, on repeated administration, selectively induce this family, thus exacerbating their carcinogenicity. CYP1 induction potency by chemicals appears to be determined by a combination of their molecular shape and electron activation. The function of cytochromes P450 in the bioactivation of chemicals is currently being exploited to design systems that can be used clinically to facilitate the metabolic conversion of prodrugs to their biologically-active metabolites in cells that poorly express them, such as tumour cells, in the so-called gene-directed prodrug therapy.
Ioannides
Costas
C
Molecular Toxicology Group, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK. c.ioannides@surrey.ac.uk
Lewis
David F V
DF
D000818:Animals; D001711:Biotransformation; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D015262:Xenobiotics / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
D002273:Carcinogens; D004364:Pharmaceutical Preparations; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System