Analysis of gene expression changes of drug metabolizing enzymes in the livers of F344 rats following oral treatment with kava extract

• Published in: Food and chemical toxicology Vol. 47; no. 2; pp. 433 - 442
• Main Authors: Guo, Lei, Li, Quanzhen, Xia, Qingsu, Dial, Stacey, Chan, Po-Chuen, Fu, Peter
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.02.2009; Elsevier
• Subjects: animal models; Animals; Biological and medical sciences; Cytochrome P-450 Enzyme System - genetics; Dietary Supplements - toxicity; Dose-Response Relationship, Drug; drug evaluation; drug metabolism; Drug metabolizing enzyme; Drug metabolizing gene; Gene expression; gene expression regulation; Gene Expression Regulation, Enzymologic - drug effects; General pharmacology; Inactivation, Metabolic - genetics; kava; Kava - chemistry; Kava - toxicity; Kava extract; liver; Liver - drug effects; Liver - enzymology; Male; Medical sciences; metabolism; Microarray; microarray technology; Oligonucleotide Array Sequence Analysis; oral administration; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Piper methysticum; Plant Extracts - toxicity; Plant poisons toxicology; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; TaqMan assay; Toxicology; Drug metabolizing gene; Kava extract; Drug metabolizing enzyme; Gene expression; Microarray; TaqMan assay; Rat; Liver; DNA chip; Extract; Medicinal plant; Gene; Dicotyledones; Angiospermae; Genetics; Drug; Digestive system; Enzyme; Rodentia; Oral administration; Piperaceae; Piper methysticum; Polymerase chain reaction; Vertebrata; Mammalia; Animal; Plant origin; Drug-metabolizing enzyme; Spermatophyta; Technique
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2008.11.037

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.