Influence of selected inhibitors on the metabolism of the styrene metabolite 4-vinylphenol in wild-type and CYP2E1 knockout mice.
4-Vinylphenol (4-VP), a minor metabolite of styrene, is a more potent hepato- and pneumotoxicant than either styrene or styrene oxide. In CD-1 mice 4-VP is metabolized primarily by cytochrome P-450 (CYP) 2E1 and CYP2F2. However, there is no difference in the rate of metabolism of 4-VP between wild-type and CYP2E1 knockout mice, indicating that other cytochromes P-450 play an important role. To understand the role of various cytochromes P-450, the in vitro metabolism of 4-VP was measured in the presence of selected inhibitors. Chemical inhibitors used to ascertain the contributions made by various cytochromes P450 were imipramine for CYP2C, alpha-methylbenzylaminobenzotriazole (MBA) for CYP2B, alpha-naphthoflavone (ANF) for CYP1A, 5-phenyl-1-pentyne (5P1P) for CYP2F2, and diethyldithiocarbamate (DTTC) for CYP2E1. Imipramine, MBA, and ANF produced significant inhibition in both the wild-type and CYP2E1 knockout mouse liver with minimal effects in lung. 5P1P significantly inhibited enzymic activity in both tissues, but to a greater extent in lung. The greatest inhibition was observed with DDTC even in the knockout mice, suggesting that it must also inhibit cytochromes P-450 in addition to CYP2E1. The results show little difference between the wild-type and knockout mice with respect to the contributions made by the cytochromes P-450 in the metabolism of 4-VP.
Carlson
Gary
G
School of Health Sciences, Purdue University, West Lafayette, Indiana 47907, USA. gcarlson@purdue.edu
D000480:Alkynes / Q000494:pharmacology; D000818:Animals; D000835:Animals, Wild; D001555:Benzene Derivatives / Q000494:pharmacology; D001571:Benzoflavones / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004050:Ditiocarb / Q000494:pharmacology; D004785:Environmental Pollutants / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010636:Phenols / Q000378:metabolism*; D020058:Styrene / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
D000480:Alkynes; D001555:Benzene Derivatives; D001571:Benzoflavones; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D010636:Phenols; D014230:Triazoles; C059849:alpha-methylbenzylaminobenzotriazole; C112922:5-phenyl-1-pentyne; D020058:Styrene; C011512:alpha-naphthoflavone; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; C030626:4-vinylphenol; D007099:Imipramine