Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid

Abstract

1. The effects of arachidonic acid on hepatic drug-metabolizing enzymes was investigated in male ICR-Swiss mice.

2. A single administration of arachidonic acid, 100 mg kg i.p., doubled the hexobarbital sleeping time. Arachidonic acid in vitro gare a type I binding spectrum with hepatic microsomes; it inhibited the metabolism of hexobarbital and of ethylmorphine, two type I binding drugs, but not that of aniline, a type II binding drug; the inhibition of hexobarbital metabolism by arachidonic acid was competitive.

3. Repeated administration of arachidonic acid up to a total dose of 1000mg kg i.p., either in the course of 5 hours, or in the course of 5 days, decreased microsomal cytochrome P-450 levels and NADPH—cytochrome c reductase activity.

4. It is concluded that the administration of arachidonic acid may impair drug metabolism in two ways, mainly, by competitively inhibiting the activity of drugmetabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.