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Phenol-induced stimulation of hydroquinone bioactivation in mouse bone marrow in vivo: possible implications in
V V Subrahmanyam1, P Doane-Setzer, K L Steinmetz
1Department of Biomedical and Environmental Health Sciences, School of Public Health, University of California, Berkeley 94720.
Abstract:
The coadministration of phenol and hydroquinone has been shown to produce myelotoxicity in mice similar to that observed following benzene exposure. One explanation of this phenomenon may be that phenol enhances the peroxidase-dependent metabolic activation of hydroquinone in the mouse bone marrow. Here we report that radiolabeled [14C]hydroquinone and [14C]phenol bind covalently to tissue macromolecules of blood, bone marrow, liver and kidney, when administered intraperitoneally to the mouse in vivo. Substantially more radiolabeled hydroquinone was covalently bound 18 h after administration as compared with that bound after 4 h. Phenol, when administered together with [14C]hydroquinone, significantly stimulated the covalent binding of [14C]hydroquinone oxidation products to blood (P less than 0.001) and bone marrow (P less than 0.05) macromolecules, but had no significant effect on covalent binding of [14C]hydroquinone oxidation products to liver and kidney macromolecules (P greater than 0.05). Catechol, on the other hand, had no effect on the binding of [14C]hydroquinone oxidation products in either bone marrow, kidney or liver (P greater than 0.05). When hydroquinone was administered together with [14C]phenol, a stimulation of the covalent binding of phenol oxidation products to bone marrow macromolecules also occurred (P less than 0.05). In addition, hydroquinone co-administration increased the covalent binding of [14C]phenol oxidation products in kidney and blood (P less than 0.05), but significantly decreased the covalent binding in liver (P less than 0.05). These results suggest that altered pharmacokinetics play a major role in the hydroquinone-dependent stimulation of covalent binding of [14C]phenol oxidation products to extrahepatic tissue macromolecules in vivo. The mechanism underlying the phenol-induced stimulation of binding of [14C]hydroquinone by phenol in blood and bone marrow remains unclear, but stimulation of peroxidase-mediated hydroquinone metabolism may be responsible. The latter may therefore play an important role in benzene-induced myelotoxicity.