TY - JOUR T1 - Comparison of Human and Rat Metabolism of Molinate in Liver Microsomes and Slices JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 842 LP - 847 VL - 27 IS - 7 AU - William T. Jewell AU - Marion G. Miller Y1 - 1999/07/01 UR - http://dmd.aspetjournals.org/content/27/7/842.abstract N2 - Molinate undergoes oxidative metabolism forming either ring-hydroxylated metabolites or molinate sulfoxide. Our previous studies strongly implicated the sulfoxidation pathway in molinate-induced testicular toxicity. The present study compares the metabolic capability of rat and human liver microsomes and slices to form either nontoxic ring-hydroxylated metabolites of molinate or the toxic metabolites derived from the sulfoxidation of molinate.Km and Vmaxvalues 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 slices reveals greater detoxification of molinate sulfoxide by glutathione conjugation 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 inhibitors. Overall, the metabolism of molinate would be via the nontoxic hydroxylation pathway in both species at low doses whereas at high doses, where sulfoxidation would predominate, the human is more capable than the rat to detoxify via glutathione conjugation. The American Society for Pharmacology and Experimental Therapeutics ER -