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 o r efficacy of drugs, provide protection from certain xenobiotic and environ mental agents, or increase toxicity of others. Cytochrome P450 (CYP450) enz ymes are responsible for the majority of oxidation reactions of drugs and o ther xenobiotics and differences in their expression may directly produce i nterindividual differences in susceptibility to compounds whose toxicity is modulated by these enzymes. To rapidly quantify CYP450 forms in human hepa tic microsomes, we developed, and applied, an ELISA to 40 samples of micros omes from adult human organ donors. The procedure was reliable and the resu lts were reproducible within normal limits. Protein content for CYP1A, CYP2 E1, 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, C YP3A was expressed in the highest amount and it was the only form whose con tent was correlated with total CYP450 content. Content of other forms was i ndependent of total CYP450. We further determined the contribution of speci fic forms to the biotransformation of trichloroethylene as a model substrat e. CYP2E1 was strongly correlated with chloral hydrate formation from trich loroethylene; CYP2B displayed the strongest correlation with trichloroethan ol formation. These data describing the expression and distribution of thes e forms in human microsomes can be used to extrapolate in vitro derived met abolic rates for toxicologically important reactions, when form selectivity and specific activity are known. This approach may be applied to refine es timates of human interindividual differences in susceptibility for applicat ion in human health risk assessment.