The site of toxicity of a number of xenobiotics and antitumor agents requiring metabolic activation is distributed in tissues containing very little P-450 monooxygenase activity. Because of the ubiquitous distribution of the prostaglandin endoperoxide synthetase (PES) system and the ability of this system to catalyze the cooxidation of xenobiotics to carcinogenic, mutagenic or other reactive species, it has been implicated to play a significant role in the metabolism of xenobiotics. We have initiated studies on the metabolism of 2-bromohydroquinone (BHQ), a compound which undergoes metabolic activation apparently independent of the P-450 monooxygenase system. BHQ is converted to reactive metabolites when incubated with PES from rat renal papilla tissue in the presence of arachidonic acid (0.08mM). Aspirin and indomethacin, inhibitors of the fatty acid cyclooxygenase component of PES and methimazole and propylthiouracil, inhibitors of the hydroperoxidase component of PES significantly decreased the formation of reactive metabolites of BHQ in rat renal papilla. The nephrotoxicity of BHQ in vivo in rats was not inhibited by the fatty acid cyclooxygenase (FAC) inhibitors aspirin and indomethacin. However, while aspirin and indomethacin were effective in inhibiting FAC, these compounds do not inhi it either the formation of hydroperoxy fatty acids via lipoxygenase pathways or the hydroperoxidase component of PES. Since lipoxygenase derived fatty acid hydroperoxides may be substrates for the hydroperoxidase, cooxidation of BHQ in vivo could occur even in the absence of prostaglandin biosynthesis. The role of the hydroperoxidase component of the PES system and other hydroperoxidase enzymes are currently under investigation.