Cytochrome P450 destruction by quinones: comparison of effects in rat and human liver microsomes

Exposure to benzene was recently reported to lower the cytochrome P450 (CYP) content in phenobarbital-pretreated rats in vivo (Gut et al., Environ. Health Perspect. 104 (1996) 1211-1218). This study followed the ability of quinonic benzene metabolites (catechol, hydroquinone, and benzoquinone) to destroy CYP in liver microsomes from rats pretreated with various inducers and in human liver microsomes. Sensitivity of CYP isoforms to destruction was revealed and the interspecies differences assessed. The spectrophotometric evaluations of the total CYP content, assay of CYP marker activities, and electrophoresis with immunoblotting after incubation of microsomes with quinones revealed that: (1) rat liver CYP activities markedly differed in sensitivity to quinone-mediated destruction in vitro, CYP 1A and 3A being the most sensitive isoforms; (2) differences in OH radicals formation and lipid peroxidation among microsomes from rats pretreated with various CYP inducers were also observed; (3) semiquinone radical formation, OH radical production, and induction of lipid peroxidation did not contribute significantly to CYP destruction by quinones; (4) the main mechanism of CYP destruction is covalent binding of the oxidized quinone form to protein and heme moieties of CYP; (5) quinones, mainly benzoquinone, destroy human CYP isoforms to a much greater extent than rat enzymes and thus humans may be much more susceptible to the deleterious effect of benzene metabolism. In conclusion, it is suggested that CYP destruction may be another consequence of benzene exposure and should be taken into consideration when evaluations of possible health risks are performed.