Radical scavenging and stimulation of prostaglandin synthesis not anti-inflammatory?

Abstract

Prostaglandins (PGs) are produced from arachidonic acid by a cascade of enzymes, the initial step being the conversion of arachidonic acid to PGG₂ by cyclooxygenase. In the next step, PGG₂ is converted to PGH₂, and it is at this stage that an oxidative radical is generated, presumably ·OH, which is capable of inactivating several enzymes of the arachidonic acid cascade^1,2. This inactivation can be prevented by radical scavengers. MK 447, a phenolic compound with such properties, was indeed found to facilitate the conversion of PGG₂ to PGH₂ and therefore to enhance PGE₂ synthesis^2,3. MK447 also inhibits irritant-induced inflammation in mice and rats; this was thought to depend on radical scavenging, which led Kuehl and colleagues to suggest that PGG₂ and ·OH are mediators of inflammation^2,3. We have tested MK447 analogues containing asymmetric centres and report here that although both antipodes were equipotent radical scavengers and stimulators of prostaglandin synthesis, only the ( + ) antipodes had anti-inflammatory and diuretic⁴ properties. This indicates that the radical scavenging properties and pharmacological actions of MK 447 and derivatives are not interdependent and questions the pro-inflammatory role of PGG₂.