Interindividual variance of cytochrome P450 forms in human hepatic microsomes: correlation of individual forms with xenobiotic metabolism and implications in risk assessment.
Differences in biotransformation activities may alter the bioavailability or efficacy of drugs, provide protection from certain xenobiotic and environmental agents, or increase toxicity of others. Cytochrome P450 (CYP450) enzymes are responsible for the majority of oxidation reactions of drugs and other xenobiotics and differences in their expression may directly produce interindividual differences in susceptibility to compounds whose toxicity is modulated by these enzymes. To rapidly quantify CYP450 forms in human hepatic microsomes, we developed, and applied, an ELISA to 40 samples of microsomes from adult human organ donors. The procedure was reliable and the results were reproducible within normal limits. Protein content for CYP1A, CYP2E1, and CYP3A positively correlated with suitable marker activities. CYP1A, CYP2B, CYP2C6, CYP2C11, CYP2E1, and CYP3A protein content demonstrated 36-, 13-, 11-, 2-, 12-, and 22-fold differences between the highest and lowest samples and the values were normally distributed. Of the forms examined, CYP3A was expressed in the highest amount and it was the only form whose content was correlated with total CYP450 content. Content of other forms was independent of total CYP450. We further determined the contribution of specific forms to the biotransformation of trichloroethylene as a model substrate. CYP2E1 was strongly correlated with chloral hydrate formation from trichloroethylene; CYP2B displayed the strongest correlation with trichloroethanol formation. These data describing the expression and distribution of these forms in human microsomes can be used to extrapolate in vitro derived metabolic rates for toxicologically important reactions, when form selectivity and specific activity are known. This approach may be applied to refine estimates of human interindividual differences in susceptibility for application in human health risk assessment.
Snawder
J E
JE
Taft Laboratory, National Institute for Occupational Safety and Health, Cincinnati, Ohio 45226, USA.
Lipscomb
J C
JC
D000328:Adult; D000368:Aged; D003577:Cytochrome P-450 Enzyme System / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D014644:Genetic Variation / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008875:Middle Aged; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment; D015262:Xenobiotics / Q000378:metabolism*
D007527:Isoenzymes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System