Prostaglandin H synthase catalyzed oxidation of hydroquinone to a sulfhydryl-binding and DNA-damaging metabolite

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Abstract
Hydroquinone, a metabolite that accumulates in bone marrow following benzene exposure, was oxidized by prostaglandin H synthase (PHS) to 1,4-benzoquinone, which was measured by HPLC with reductive electrochemistry. Hydroquinone metabolism in the presence of cysteine generated a thiol adduct, which was identified as the monosubstituted cysteine conjugate of hydroquinone by HPLC with oxidative electrochemical and radiochemical detection. The time-dependent formation of both 1,4-benzoquinone and the monocysteine-hydroquinone conjugate was monitored spectrophotometrically at 250 and 305 nm, respectively. Monocysteine-hydroquinone was formed at rates similar to 1,4-benzoquinone formation in reactions without cysteine, suggesting that 1,4-benzoquinone or its semiquinone intermediate is rapidly binding to sulfhydryls. The PHS-catalyzed activation of hydroquinone to 1,4-benzoquinone or its thiol conjugate required the presence of either arachidonic acid or H2O2. The oxidative metabolism of hydroquinone also resulted in the formatin of a reactive product(s) that irreversibly bound to DNA. This binding was time dependent and did not occur in the presence of heat-inactivated PHS. Metabolite(s) generated during hydroquinone oxidation also induced single-strand breaks in Bluescript plasmid DNA. The PHS/arachidonic acid catalyzed metabolism of hydroquinone to 1,4-benzoquinone and to product(s) that bound to sulfhydryls and DNA and caused strand breaks in DNA was prevented by indomethacin, an inhibitor of PHS cyclooxygenase. Because prostaglandin synthesis is elevated in bone marrow following benzene exposure and inhibitors of PHS cyclooxygenase prevent benzene-induced myelotoxicity, the activation of hydroquinone by PHS represents a possible mechanism for benzene''s effects.