The inhibitory effect of polyunsaturated fatty acids on human CYP enzymes.

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Yao HT, Chang YW, Lan SJ, Chen CT, Hsu JT, Yeh TK

The inhibitory effect of polyunsaturated fatty acids on human CYP enzymes.

Life Sci. 2006 Nov 25;79(26):2432-40. Epub 2006 Aug 23.

PubMed ID

16978661 [ View in PubMed

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Abstract

The inhibitory effect of saturated fatty acids (SFAs): palmitic acid (PA), stearic acid (SA) and polyunsaturated fatty acids (PUFAs): linoleic acid (LA), linolenic acid (LN), arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on six human drug-metabolizing enzymes (CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4) was studied. Supersomes from baculovirus-expressing single isoforms were used as the enzyme source. Phenacetin O-deethylation (CYP1A2), diclofenac 4-hydroxylation (CYP2C9), mephenytoin 4-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1) and midazolam 1-hydroxylation (CYP3A4) were used as the probes. Results show that all the five examined PUFAs competitively inhibited CYP2C9- and CYP2C19-catalyzed metabolic reactions, with Ki values ranging from 1.7 to 4.7 microM and 2.3 to 7.4 microM, respectively. Among these, AA, EPA and DHA tended to have greater inhibitory potencies (lower IC(50) and Ki values) than LA and LN. In addition, these five PUFAs also competitively inhibited the metabolic reactions catalyzed by CYP1A2, 2E1 and 3A4 to a lesser extent (Ki values>10 microM). On the other hand, palmitic and stearic acids, the saturated fatty acids, had no inhibitory effect on the activities of six human CYP isozymes at concentrations up to 200 microM. Incubation of PUFAs with CYP2C9 or CYP2C19 in the presence of NADPH resulted in the decrease of PUFA concentrations in the incubation mixtures. These results indicate that the PUFAs are potent inhibitors as well as the substrates of CYP2C9 and CYP2C19.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Doconexent	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate Inhibitor	Details