Prostaglandin H synthase-1 (PGHS-1) is the key enzyme in the biosynthesis of prostaglandins, homeostatic lipid mediators in the cardiovascular, gastrointestinal, renal and other organ systems. PGHS-2, on the other hand, is a separate gene product, is highly regulated, inducible and is regarded as the form involved in cancer and inflammation. While the simplistic viewpoint of """"""""housekeeping"""""""" PGHS-l vs """"""""inducible, pro-inflammatory"""""""" PGHS-2 is practical, data is emerging that is not entirely consistent with this hypothesis. PGHS isozymes are bifunctional, with a cyclooxygenase (COX) activity and a functionally linked peroxidase (POX) activity. Non-steroidal antiinflammatory drugs (NSAIDs) act by inhibition of the COX activity, leaving POX activity intact. Substantial data, primarily from in vitro model systems, has implicated the POX component of PGHS in the metabolic activation of xenobiotics and other non-prostaglandin related activities. The main objective of this proposal is to delineate the distinct functions of the COX and POX activities of the PGHS isozymes in carcinogenesis and inflammation using mice with induced mutations created by gene targeting in embryonic stem cells.
In Aim 1, COX gene-disrupted mice will be generated by mutation of the aspirin-binding site (serine 530 to asparagine or glutamine), while POX gene-disrupted mice will be created via mutation of the proximal heme ligand (histidine 388 to tyrosine) in Aim 3. The involvement of PGHS POX in the metabolic activation of the nitrofuran compound FANFT, a potent urinary bladder carcinogen, will be analyzed by examination of tumor formation in the mutant mice. Also, the effects of separate COX and POX ablation on skin carcinogenesis using the two-stage DMBA/phorbol ester initiation/promotion protocol and models of inflammation will be assessed in Aims 2 and 4. The COX-disrupted mice, in essence, are perfect in vivo models for complete and selective PGHS-1 arid PGHS-2 inhibition and will be invaluable for studying non-PGHS dependent actions of NSAIDs. Results obtained from this proposal should have broad implications for understanding mechanisms of human cancer and inflammatory disease.
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