The COX Concept

Journal/Book: Z Rheumatol 1998; 57 Suppl. 1: 12 (V 41). 1998;

Abstract: The William Harvey Research Institute St. Bartholomew's and the Royal London School of Medicine and Dentistry Queen Mary and Westfield College London The cyclooxygenase enzyme purified in 1976 and cloned in 1988 is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991 several laboratories identified an enzyme with cyclooxygenase activity derived from a second gene and named it COX-2. Only COX-2 was inducible and the inducing stimuli included pro-inflammatory cytokines and growth factors implying a role for COX-2 both in inflammation and in control of cell growth. The two isoforms of COX are almost identical in structure but exhibit important differences in substrate preference inhibitor selectivity and in their intracellular localisations. Protective PGs which help to preserve the integrity of the stomach mucosa and which maintain renal function in a compromised kidney are synthesized by COX-1. Pro-inflammatory PGs produced in arthritic joints are formed by COX-2 induced with inflammatory mediators. In addition to the induction of COX-2 in inflammatory lesions it is present constitutively in the brain and spinal cord where it may be involved in neuronal transmission particularly that for pain and fever. Prostaglandins made by COX-2 are also important in ovulation and the birth process. The mechanism of action of the non-steroid anti-inflammatory drugs was elucidated in 1971 when Vane discovered that aspirin and indomethacin inhibited the synthesis of prostaglandins. Subsequently many more aspirin-like drugs were developed. They all inhibit both COX-1 and COX-2 but to different degrees. The discovery of COX-2 has made possible the design of drugs which reduce inflammation without removing the protective PGs made by COX-1 in the stomach and kidney. ... le

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