PHASE-II METABOLISM OF BENZENE

The hepatic metabolism of benzene is thought to be a prerequisite for its bone marrow toxicity. However, the complete pattern of benzene met abolites formed in the liver and their role in bone marrow toxicity ar e not fully understood. Therefore, benzene metabolism was studied in i solated rodent hepatocytes. Rat hepatocytes released benzene-1,2-dihyd rodiol. hydroquinone (HQ), catechol (CT), phenol (PH), trans-trans-muc onic acid, and a number of phase II metabolites such as PH sulfate and PH glucuronide. Pretreatment of animals with 3-methylcholanthrene (3- MC) markedly increased PH glucuronide formation while PH sulfate forma tion was decreased. Likewise, V79 cells transfected with the 3-MC-indu cible rat UGT1.6 cDNA showed a considerable rate of PH and HQ glucuron idation. In addition to inducing glucuronidation of phenols, 3-MC trea tment (reported to protect rats from the myelotoxicity of benzene) res ulted in a decrease of hepatic CYP2E1. In contrast, pretreatment of ra ts with the CYP2E1-inducer isopropanol strongly enhanced benzene metab olism and the formation of phenolic metabolites. Mouse hepatocytes for med much higher amounts of HQ than rat hepatocytes and considerable am ounts of 1,2,4-trihydroxybenzene (THB) sulfate and HQ sulfate. In conc lusion, the protective effect of 3-MC in rats is probably due to a shi ft from the labile PH sulfate to the more stable PH glucuronide, and t o a decrease in hepatic CYP2E1. The higher susceptibility of mice towa rd benzene may be related to the high rate of formation of the myeloto xic metabolite HQ and the semistable phase II metabolites HQ sulfate a nd THE sulfate.