Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs.
The principal pharmacological effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to their ability to inhibit prostaglandin synthesis. NSAIDs block the cyclooxygenase activities of the closely related PGH synthase-1 and PGH synthase-2 (PGHS-1 and PGHS-2) isozymes. NSAIDs are therapeutically useful due to their analgesic, anti-pyretic, anti-inflammatory, and anti-thrombogenic properties. Major side-effects of NSAIDs include their ulcerogenic and nephrotoxic activities. All clinically approved NSAIDs in general use today inhibit both PGHS-1 and PGHS-2. Recently, inhibitors have been identified that are selective toward PGHS-2 and that have potent analgesic and anti-inflammatory activities with minimal ulcerogenic activity. If the new PGHS-2 selective NSAIDs can effectively inhibit inflammatory prostaglandin synthesis by PGHS-2, without inhibiting PGHS-1 prostaglandin synthesis required to regulate sodium and water resorption, and renal blood flow, it is likely that these new drugs will also have significantly less renal toxicity than present-day NSAIDs. In this article, the mechanisms of actions of NSAIDs primarily at the biochemical level, including the reactions catalyzed by PGHSs, will be discussed. In addition, the biochemical properties of these isozymes, and the differential regulation of the PGHS-1 and PGHS-2 genes, will be examined.
Smith
W L
WL
Department of Biochemistry, Michigan State University, East Lansing, USA.
DeWitt
D L
DL
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000145:classification / Q000494:pharmacology*; D001665:Binding Sites; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D011451:Prostaglandin-Endoperoxide Synthases