Cooxidation by Cyclooxygenases

The cyclooxygenase (COX) enzyme is known to exist as two distinct isoforms. COX-1 is a constitutively expressed housekeeping enzyme found in nearly all tissues and mediates physiological responses. COX-2 is an inducible form expressed primarily by cells involved in the inflammatory response. Several tissues low in CYP expression are rich in COX, which is believed to have significance in the carcinogenic effects of aromatic amines in these organs. 

During cooxidation, some substrates are activated to become more toxic than they were originally. In some cases substrate oxidation results in the production of free radicals, which may initiate lipid peroxidation or bind to cellular proteins or DNA. Another activation pathway involves the formation of a peroxyl radical from subsequent metabolism of prostaglandin G2. This reactive molecule can epoxidize many substates including polycyclic aromatic hydrocarbons, generally resulting in increasing toxicity of the respective substrates. 

To differentiate between xenobiotic oxidations by COX and CYP, in vitro microsomal incubations of the xenobiotic may be performed either in the presence of arachidonic acid (COX catalyzed) or in the presence of NADPH (CYP catalyzed). In the presence of arachidonic acid while in the absence of NADPH, substrates co-oxidized by COX will be formed while those requiring CYP will not. Specific inhibitors of PG synthase (indomethacin) and CYP (Metyrapone or SKF 525A) have also been used. 

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