Metabolism of benzene in human liver microsomes: individual variations in relation to CYP2E1 expression

In human liver microsomes the oxidations of benzene, chlorzoxazone, aniline , dimethylformamide, and 4-nitrophenol were significantly correlated with e ach other and with the level of cytochrome P450 (CYP) 2E1 estimated by immu noblotting. Moreover, benzene oxidation to water-soluble metabolites was su ppressed by 0.1 mM diethyldithiocarbamate, supposedly a specific inhibitor of CYP2E1 at this level, None of these metabolic rates correlated with immu nochemically determined levels of CYP1A2, 2C9, and 3A4 nos oxidation of 7-e thoxyresorufin, tolbutamide, and nifedipine. Benzene oxidation to water-sol uble metabolites was characterized by typical Michaelis-Menten kinetics. Th e different benzene K-m values seen in individual human microsomal samples were not correlated with the level or activity of CYP1A2, 2C9, 2E1, and 3A4 but could be due to CYP2E1 microheterogeneity. The lowest K-m for benzene oxidation could be related to C/D and/or c1/c2 polymorphism of CYP2E1 gene. Covalent binding of benzene reactive metabolites to microsomal proteins wa s also correlated with the CYP2E1 metabolic rates and immunochemical levels . At high concentrations of benzene covalent binding was inversely related to benzene concentrations (as well as to formation of water-soluble metabol ites) in agreement with the view that secondary metabolites, mainly benzoqu inone, are responsible for the covalent binding.