國家衛生研究院 NHRI:Item 3990099045/1239

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Title:	The inhibitory effect of polyunsaturated fatty acids on human CYP enzymes
Authors:	Yao, HT;Chang, YW;Lan, SJ;Chen, CT;Hsu, JTA;Yeh, TK
Contributors:	Division of Biotechnology and Pharmaceutical Research
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 mu M and 2.3 to 7.4 mu M, respectively. Among these, AA, EPA and DHA tended to have greater inhibitory potencies (lower IC50 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 mu M). On the otherhand, 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 mu M. 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. (c) 2006 Elsevier Inc. All rights reserved.
Keywords:	Medicine, Research & Experimental;Pharmacology & Pharmacy
Date:	2006-11-25
Relation:	Life Sciences. 2006 Nov;79(26):2432-2440.
Link to:	http://dx.doi.org/10.1016/j.lfs.2006.08.016
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0024-3205&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000242565600002
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=33751205342
Appears in Collections:	[Teng-Kuang Yeh] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Chiung-Tong Chen] Periodical Articles

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