Comparison of human and rat metabolism of molinate in liver microsomes andslices

Molinate undergoes oxidative metabolism forming either ring-hydroxylated me tabolites or molinate sulfoxide. Our previous studies strongly implicated t he sulfoxidation pathway in molinate-induced testicular toxicity. The prese nt study compares the metabolic capability of rat and human liver microsome s and slices to form either nontoxic ring-hydroxylated metabolites of molin ate or the toxic metabolites derived from the sulfoxidation of molinate. K- m and V-max values indicate that sulfoxidation would be the preferred high- dose pathway whereas hydroxylation would predominate at low dose levels in both species. Examination of phase II metabolism of molinate in liver slice s reveals greater detoxification of molinate sulfoxide by glutathione conju gation in humans with rats forming less conjugate. Oxidative metabolism of molinate in both rats and humans appears to be mediated by cytochrome P-450 and not flavin monooxygenases as indicated by the use of metabolic inhibit ors. Overall, the metabolism of molinate would be via the nontoxic hydroxyl ation pathway in both species at low doses whereas at high doses, where sul foxidation would predominate, the human is more capable than the rat to det oxify via glutathione conjugation.