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

Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley, California 94720

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 oxidative DNA damage) and induce genotoxic effects. Here we report the induction of oxidative DNA damage by benzene and its phenolic metabolites in HL60 cells in vitro and in the bone marrow of C57BL/6 x C3H F₁ mice in vivo utilizing 8-hydroxy-2'-deoxyguanosine as a marker. HL60 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 1 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 significant increases in steady state levels of oxidative DNA damage in the mouse bone marrow but were not effective when administered individually. Administration of 1,2,4-benzenetriol alone did, however, result in a significant increase in oxidative DNA damage. This represents the first direct demonstration of active oxygen production by benzene and its phenolic metabolites in vivo. The conversion of benzene to phenolic metabolites and the subsequent production of oxidative DNA damage may therefore play a role in the benzene-induced genotoxicity, myelotoxicity, and leukemia.

¹ Supported by Grants P42ES04705 and P30ES01896 from the National Institute of Environmental Health Sciences. P. K. and K. B. M. are trainees of the Health Effects Component of the UC Toxic Substances Program. L. Z. is supported by the William and Ada Isabell Steel Memorial Graduate Scholarship from Simon Fraser University, Burnaby, British Columbia, Canada.

² Present address: Department of Drug Metabolism and Pharmacokinetics, American Cyanamid Company, Pearl River, NY 10965.

³ Permanent address: Bioenergetic Research Laboratory, Faculty of Applied Science, Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6.

⁴ To whom requests for reprints should be addressed, at Department of Biomedical and Environmental Health Sciences, School of Public Health, 322-Warren Hall, University of California, Berkeley, CA 94720.

Received 9/24/92. Accepted 12/22/92.

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