Human cytochromes P450

Arachidonic acid and many products of the arachidonate cascade serve as substrates for cytochrome P450-mediated metabolism via allylic oxidation, omega hydroxylation, and epoxygenation as well as peroxide rearrangement. Defining the physiological importance of these metabolites is an area of intense research interest. Cytochrome P450-catalyzed reactions play prominent roles in multiplying the structural and functional diversity of the arachidonate metabolic cascade.

Cytochrome P450 and the arachidonate cascade.

The Inhibitory Effect of Polyunsaturated Fatty Acids on Human CYP Enzymes

Eukaryotic cells contain substantial amounts of arachidonic acid (AA; 5,8,11,14-eicosatetraenoic acid) esterified predominantly to the sn-2 position of cellular glycerophospholipids. As with many lipid-derived mediators, e.g., cholesterol, phosphoinositides, diglycerides, AA serves a structural role, as a component of cellular membranes, and an important functional role, as a participant in a variety of receptor/agonist-mediated signaling cascades.1–4 In the absence of stimuli, the intracellular levels of nonesterified AA are nearly undetectable. However, most organ cells possess an elaborate enzymatic machinery that, in response to a variety of stimuli, catalyzes: (1) the hydrolytic cleavage of the AA molecule form selected, hormonally sensitive phospholipid pools, (2) the transduction of chemical information into the fatty acid molecular template by means of regio- and stereospecific oxygenation reactions, and (3) the decoding of that chemical information either by receptor-mediated processes or, alternatively, by the direct effects of these oxygenated metabolites on metabolic pathways1–4 (Fig. 1). As a net result, these processes provide cells with a rapid and versatile on/off molecular switch for the intra- or intercellular transduction and/or amplification of functionally meaningful information.

Cytochrome P450 and the Metabolism of Arachidonic Acid and Oxygenated Eicosanoids

Cytochrome P450 and the Metabolism of Arachidonic Acid and Oxygenated

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.

Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid.

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Inhibition of hepatic drug-metabolizing enzymes by arachidonic acid.