Pharmacokinetic interaction between benzene metabolites, phenol and hydroquinone, in B6C3F1 mice

There is strong evidence that metabolites are responsible for adverse effects of benzene. Benzene myelotoxicity, reproduced by coadministering phenol (PH) and hydroquinone (HQ) but not when these benzene metabolites were administered alone, has been postulated to be induced by PH stimulating the myeloperoxidase-mediated oxidation of HQ to the toxic 1,4-benzoquinone in bone marrow. A pharmacokinetic interaction between PH and HQ is also hypothesized to contribute to the observation. Both metabolites are sulfoconjugated and glucuronoconjugated. Sulfoconjugation of phenolic substrates has been shown to approach saturation at high concentrations in rats. Thus, more PH may be converted to HQ and HQ conjugation may be diminished. These effects would increase the amounts of PH and HQ present and result (by further oxidation) in the formation of more 1,4-benzoquinone. To test this hypothesis, we investigated the pharmacokinetics in blood and the recovery of hydroquinone and phenol in urine when the metabolites were administered intraperitoneally alone or in combination at 75 mg/kg each to B6C3F1 mice. The combination resulted in a 2.6-fold increase in the area under the blood concentration-time curve (AUC) of HQ compared to the sum of AUC values observed after administration of each compound alone. The half-life of HQ was also increased from 9 +/- 2 to 15 +/- 3 min. The AUC of PH was increased by a factor of 1.4. The clearance of phenol decreased from 89 +/- 13 ml/min per kilogram when injected alone to 62 +/- 7 ml/min per kilogram after coadministration. A decreased clearance of formation of each conjugate demonstrated that both conjugation pathways were diminished. This interaction may contribute to the observed production of myelotoxicity when these metabolites are coadministered.