title: Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract.
abstract: The association of kava product use with liver-related risks has prompted regulatory action in many countries. We studied the changes in gene expression of drug metabolizing enzymes in the livers of Fischer 344 male rats administered kava extract by gavage for 14 weeks. Analysis of 22,226 genes revealed that there were 14, 41, 110, 386, and 916 genes significantly changed in the 0.125, 0.25, 0.5, 1.0, and 2.0 g/kg treatment groups, respectively. There were 16 drug metabolizing genes altered in all three high-dose treatment groups, among which seven genes belong to cytochrome P450 isozymes. While gene expression of Cyp1a1, 1a2, 2c6, 3a1, and 3a3 increased; Cyp 2c23 and 2c40 decreased, all in a dose-dependent manner. Real-time PCR analyses of several genes verified these results. Our results indicate that kava extract can significantly modulate drug metabolizing enzymes, particularly the CYP isozymes, which could cause herb-drug interactions and may potentially lead to hepatotoxicity.
authors.affiliation: Division of Systems Toxicology, National Center for Toxicological Research, FDA, 3900 NCTR Road, Jefferson, AR 72079, USA. lei.guo@fda.hhs.gov
authors.forename: Lei
authors.initials: L
authors.lastname: Guo
authors.forename: Quanzhen
authors.initials: Q
authors.lastname: Li
authors.forename: Qingsu
authors.initials: Q
authors.lastname: Xia
authors.forename: Stacey
authors.initials: S
authors.lastname: Dial
authors.forename: Po-Chuen
authors.initials: PC
authors.lastname: Chan
authors.forename: Peter
authors.initials: P
authors.lastname: Fu
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D019587:Dietary Supplements / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D008658:Inactivation, Metabolic / Q000235:genetics; D020901:Kava / Q000737:chemistry / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010936:Plant Extracts / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010936:Plant Extracts; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System