Molecular regulation of prostaglandin synthesis Implications for endocrine systems.

A wide array of prostanoids, which includes prostaglandins D(2), E(2), F(2alpha), I(2), and thromboxane A(2), has been known to exert regulatory effects in many endocrine systems for over 3 decades. More recently, however, molecular biological techniques have uncovered new findings that have brought about radical changes in our thinking about prostaglandin pharmacology and physiology. Two separate forms of cyclooxygenase (COX), a constitutive and an inducible form, have been identified. These two forms arise from separate genes whose expression is regulated differently. Moreover, genes for different receptor types and sub-types of prostanoid receptors have also been cloned. The various prostanoid receptor types and subtypes are coupled to transduction systems that cause alterations in intracellular calcium and cAMP concentrations. As importantly, new sites of inhibitory action for corticosteroids and nonsteroidal antiinflammatory drugs in the COX-2 synthetic pathway have been uncovered that decrease COX-2 mRNA levels and enzyme mass. Most of the nonsteroidal antiinflammatory drugs are more effective in inhibiting activity of COX-1 compared with COX-2. This carries important clinical relevance, because COX-1 is proposed to play a role in normal physiologic processes rather than in mediating inflammation, which may explain the undesirable side effects of some of these drugs. Possible implications of these new developments on regulation of bone resorption as a representative endocrine system are considered.