Influence of Selected Inhibitors on the Metabolism of the Styrene Metabolite 4-Vinylphenol in Wild-Type and CYP2E1 Knockout Mice

Abstract

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, α-methylbenzylaminobenzotriazole (MBA) for CYP2B, α-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.