Intra-individual variation of cytochrome p450 forms in human hepatic microsomes: correlation of individual forms with xenobiotic metabolism.
Toxicologist 1997 Mar; 36(1)(Part 2):25
We and others have previously demonstrated that P-450 dependent trichlorethylene (TRI) metabolism is highest in microsomes from mice, somewhat lower in rats and substantially lower in pooled human microsomes. In this study we report on levels of 6 P450 forms (as measured by a direct ELISA) and microsomal metabolism toward TRI in relation to specific content of P450 forms in these samples. Cytochrome P450 forms were quantified in human microsomes using antibodies specific to rat P450s CYP1A, CYP2B, CYP2C6, CYP2C11, CYP2E1 and CYP3A. Protein content for CYP1A, CYP2E1 and CYP3A were positively correlated with microsomal activities that are recognized as suitable markers for those forms. CYP1A content varied approximately 5 fold between the highest and lowest human samples tested. CYP2B, CYP2C6-reactive proteins, CYP2E1 and CYP3A demonstrated approximately 10-fold differences between the highest and lowest samples. CYP2C11-reactive microsomal protein displayed minimal differences in content among the samples tested. P450 content of specific P450 forms was not correlated to total P450. When comparing levels of specific P450 forms to TRI metabolism, CYP2E1 was strongly correlated to high TRI-Vmax and chloral hydrate formation; whereas CYP2B displayed the strongest correlation toward formation of trichloroethanol. These results indicate that humans are not uniform in their capacity to metabolize TRI, and that factors which result in increased CYP2E1 and/or CYP2B activity may increase susceptibility to TRI-induced toxicity in the human.
Laboratory-animals; Animal-studies; Animals; Microsomal-enzymes; Microscopic-analysis; Toxins; Toxic-materials; Toxic-effects
The Toxicologist. Society of Toxicology 36th Annual Meeting, March 9-13, 2006, Cincinnati, Ohio