Individual Prostaglandins

Figure 1. Role of cyclooxygenase (COX) in prostaglandin synthesis.

Laboratory studies using COX-1 and COX-2 deficient mice, and COX-specific inhibitors suggest there are some biological events in which distinct COX isoenzymes are involved (Table 1), some in which they act together, and others where one isoenzyme can compensate if the other is lacking. There are also likely to be unique prostanoid synthetic pathways for COX-1 and COX-2, via designated coupling to various downstream prostaglandin synthases (14).

A specific PGE synthase has been identified which is induced with COX-2 and may function preferentially with it rather than with COX-1 (15, 16).

Some insight into the biological roles of COX-2 has been gained from animal studies.

COX-2 null mice are infertile, and although COX-2 deficient mice undergo follicular development, they demonstrate a marked reduction in ovulation, and in the release of fertilised eggs (17, 18). This may be caused by a deficiency of ovarian PGE2, as exogenous supplementation of this prostaglandin restores ovulatory function (19). COX-2 deficiency also retards implantation of the blastocyst (18), and disrupts renal development. Affected mice develop severe renal disease, which has a different pathology from NSAID-induced renal toxicity (17, 20).

COX-2 has been implicated in development of the cardiovascular system (21). Nearly 35% of COX-2 null mice die within 48 hours of birth of birth due to a patent ductus arteriosus.

Both COX isoenzymes also subserve critical roles during T-cell development in the developing thymus, and COX-2 may have a specific influence on CD4 cell differentiation (22).

COX isoenzymes also activate cellular signalling reactions which involve electron transfer (reduction/oxidation or "redox") reactions. This is via an intrinsic, highly active peroxidase (POX) activity (23, 24). The COX and POX activities are physically and functionally separate (4).

A variety of substrates are oxidised by the POX component, some are carcinogenic and lead to the production of more mutagens (25).

Significantly, POX activity is not necessarily blocked by NSAIDs (4), and selective COX-2 inhibitors also have little effect against POX activity. Steroids, however, due to their effects on transcription, downregulate total cellular COX-2 protein content, and cause a fall in both activities (3).

Table 1. important biological roles of the COX isoenzymes

Isoenzyme Biological roles

COX-1 Parturition, platelet aggregation

COX-2 Ovulation, implantation, perinatal renal development, remodelling of the ductus arteriosus. Compensatory effects COX-1 can compensate for COX-2 deficiency in parturition and closure of the ductus arteriosus Both T-cell development, protection against gastric ulceration.

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