Benzene and Its Phenolic Metabolites Produce Oxidative DNA Damage in HL60 Cells in Vitro and in the Bone Marrow in Vivo1

Benzene, an important industrial chemical, is myelotoxic and leukemogenic in humans. It is metabolized by cytochrome P450 2E1 to various phenolic metabolites which accumulate in the bone marrow. Bone marrow contains high levels of myeloperoxidase which can catalyze the further metabolism of the phenolic metabolites to reactive free radical species. Redox cycling of these free radical species produces active oxygen. This active oxygen may damage cellular DNA (known as oxidalive DNA dam age) and induce genotoxic effects. Here we report the induction of oxidative DNA damage by benzene and its phenolic metabolites in HIM) cells in vitro and in the bone marrow of C57BL/6 x C3H F, mice in vivo utilizing 8-hydroxy-2'-deoxyguanosine as a marker. III.Ml cells (a human leukemia cell line) contain high levels of myeloperoxidase and were used as an in vitro model system. Exposure of these cells to phenol, hydroquinone, and 1,2,4-benzenetriol resulted in an increased level of oxidative DNA damage. An increase in oxidative DNA damage was also observed in the mouse bone marrow in vivo l h after benzene administration. A dose of 200 mg/kg benzene produced a 5-fold increase in the 8-hydroxydeoxyguanosine level. Combinations of phenol, catechol, and hydroquinone also resulted in sig nificant increases in steady state levels of oxidative DNA damage in the mouse bone marrow but were not effective when administered individu ally. Administration of 1,2,4-benzenetriol alone did, however, result in a significant increase in oxidative DNA damage. This represents the tirsi direct demonstration of active oxygen production by benzene and its phenolic metabolites in rim. The conversion of benzene to phenolic me tabolites and the subsequent production of oxidative DNA damage may therefore play a role in the benzene-induced genotoxicity, myelotoxicity,