Metabolic rate constants for hydroquinone in F344 rat and human liver isolated hepatocytes: application to a PBPK model.

Hydroquinone (HQ) is an important industrial chemical that also occurs naturally in foods and in the leaves and bark of a number of plant species. Exposure of laboratory animals to HQ may result in species-, sex-, and strain-specific nephrotoxicity. The sensitivity of male F344 versus female F344 and Sprague-Dawley rats or B6C3F1 mice appears to be related to differences in the rates of formation of key nephrotoxic metabolites. Metabolic rate constants for the conversion of HQ through several metabolic steps to the mono-glutathione conjugate and subsequent detoxification via mercapturic acid formation were measured in suspension cultures of hepatocytes isolated from male F-344 rats and humans. A mathematic kinetic model was used to analyze each metabolic step by simultaneously fitting the disappearance of each substrate and the appearance of subsequent metabolites. An iterative, nested approach was used whereby downstream metabolites were considered first, and the model was constrained by the requirement that rate constants determined during analysis of individual steps must also satisfy the complete, integrated metabolism scheme, including competitive pathways. The results from this study indicated that the overall capacity for metabolism of HQ and its mono-glutathione conjugate is greater in hepatocytes from humans than in those from rats, suggesting a greater capacity for detoxification of the glutathione conjugates in humans. Metabolic rate constants were applied to an existing physiologically based pharmacokinetic model, which was used to predict total glutathione metabolites produced in the liver. The results showed that body burdens of these metabolites will be much higher in rats than in humans.