Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid.
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 gave 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 1000 mg/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 drug-metabolizing enzymes, and secondarily, by decreasing the hepatic concentration of these enzymes.
D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006591:Hexobarbital / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
D001095:Arachidonic Acids; D003577:Cytochrome P-450 Enzyme System; D006591:Hexobarbital; D006899:Mixed Function Oxygenases; D010088:Oxidoreductases; D009251:NADPH-Ferrihemoprotein Reductase