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 synthase (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 as playing a significant role in the metabolism of xenobiotics. We have initiated studies on the metabolism of a variety of compounds by ram seminal vesicle (RSV) microsomes (a rich source of PES). These compounds include: a) anticancer agents, such as NMF, cytoxan, PCNU, AZQ, caracemide and mitoxantrone; b) a pulmonary toxin, ipomeanol; and c) nephrotoxins such as o-bromophenol and 2-bromohydroquinone. During prostaglandin biosynthesis, mitoxantrone, o-bromophenoland 2-bromohydroquinone were cooxidized to reactive metabolites which then bound to RSV microsomal protein. Furthermore, two of the human lung carcinoma cell lines containing high PES activity are susceptible to mitroaxantrone induced cytotoxicity. The degree of cytotoxicity induced by mitoxantrone correlates with the PES activity in these two cell lines. The mechanisms(s) of PES-mediated cooxidation and toxicity of antitumor agents and other xenobiotics in human lung carcinoma-derived cells are currently under investigation. The utilization of homogenous human lung carcinoma cells systems for systematic screening of anticancer drugs directed at the PES system may provide hope for achieving target cell mediated atineoplastic effectiveness in lung cancer therapy.