Identification of Quinol Thioethers in Bone Marrow of Hydroquinone/Phenol-Treated Rats and Mice and Their Potential Role in Benzene-Mediated Hematotoxicity

Abstract

Metabolism of benzene is required to produce the classical hematological disorders associated with its exposure. After coadministration of hydroquinone (0.9 mmol/kg, ip) and phenol (1.1 mmol/kg, ip) to male Sprague−Dawley rats and DBA/2 mice, 2-(glutathion-S-yl)hydroquinone was identified in the bone marrow of both species. 2,5-Bis(glutathion-S-yl)hydroquinone, 2,6-bis(glutathion-S-yl)hydroquinone, and 2,3,5-tris(glutathion-S-yl)hydroquinone were also observed in the bone marrow of rats but were detected only sporadically in mice. Both species produced 2-(cystein-S-ylglycinyl)hydroquinone, 2-(cystein-S-yl)hydroquinone, and 2-(N-acetylcystein-S-yl)hydroquinone, indicating the presence of a functional mercapturic acid pathway in bone marrow. The ability of bone marrow to acetylate 2-(cystein-S-yl)hydroquinone and deacetylate 2-(N-acetylcystein-S-yl)hydroquinone was confirmed in vitro. Total quinol thioether concentrations were higher in, and eliminated more slowly from, the bone marrow of mice. Intravenous injection of 100 μmol/kg 2-(glutathion-S-yl)hydroquinone to rats gave rise to substantially lower bone marrow C_max and AUC values compared to values found following coadministration of hydroquinone/phenol, suggesting that the major fraction of the GSH conjugates present in bone marrow are formed in situ. Finally, the erythrotoxicity of several of these conjugates was determined in rats using the erythrocyte ⁵⁹Fe incorporation assay. Administration of 2,3,5-tris(glutathion-S-yl)hydroquinone (17 μmol/kg, iv), 2,6-bis(glutathion-S-yl)hydroquinone (50 μmol/kg, iv), and benzene (11 mmol/kg, sc) significantly decreased ⁵⁹Fe incorporation into reticulocytes to 45 ± 6%, 28 ± 3%, and 20 ± 9% of control values, respectively. Although the doses of 2,3,5-tris(glutathion-S-yl)hydroquinone and 2,6-bis(glutathion-S-yl)hydroquinone represented only 0.2% and 0.4% of the dose of benzene, both conjugates reduced ⁵⁹Fe incorporation to the same degree as benzene. 2-(Glutathion-S-yl)hydroquinone had no effect at the dose tested (200 μmol/kg, iv). In summary, these data suggest that hydroquinone−glutathione conjugates are erythrotoxic and may contribute to benzene-mediated hematotoxicity.