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ToxSci Advance Access originally published online on February 27, 2007
Toxicological Sciences 2007 97(1):214-221; doi:10.1093/toxsci/kfm035
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Effects of Kava Alkaloid, Pipermethystine, and Kavalactones on Oxidative Stress and Cytochrome P450 in F-344 Rats

Steven T.S. Lim*, Klaus Dragull{dagger}, Chung-Shih Tang{dagger}, Harry C. Bittenbender{ddagger}, Jimmy T. Efird§ and Pratibha V. Nerurkar*,1

* Laboratory of Metabolic Disorders and Alternative Medicine, Department of Molecular Biosciences and Bioengineering {dagger} Department of Molecular Biosciences and Bioengineering {ddagger} Department of Tropical Plant and Soil Sciences, College of Tropical Agriculture and Human Resources, University of Hawaii at Manoa, Honolulu, Hawaii 96822 § Biostatistics and Data Management Facility, Asia-Pacific Institute of Tropical Medicine and Infectious Diseases, John A. Burns School of Medicine, Honolulu, Hawaii 96813

1 To whom correspondence should be addressed at Laboratory of Metabolic Disorders and Alternative Medicine, Department of Molecular Biosciences and Bioengineering, College of Tropical Agriculture and Human Resources, Room 218, Agriculture Science Building, 1955 East-West Road, University of Hawaii at Manoa, Honolulu, HI 96822. Fax: (808) 956-3542. E-mail: pratibha{at}hawaii.edu.

Received January 22, 2007; accepted February 19, 2007


  Abstract

Kava-containing products remain popular in the United States and continue to be sold in health food stores and ethnic markets regardless of the fact that it was banned in Western countries such as Germany, France, Switzerland, Australia, and Canada, following reports of alleged hepatotoxicity. It is therefore critical to establish efficacy and verify adverse effects and/or herb-drug interactions for kava-kava (Piper methysticum). We have previously demonstrated that kava alkaloid, pipermethystine (PM), abundant in leaves and stem peelings, induces mitochondrial toxicity in human hepatoma cells, HepG2, as compared with the bioactive components, kavalactones (KL), abundant in the rhizome. The current study compared short-term toxic effects of PM in Fischer-344 (F-344) rats to acetone-water extracts of kava rhizome (KRE). Treatment of F-344 rats with PM (10 mg/kg) and KRE (100 mg/kg) for 2 weeks failed to elicit any significant changes in liver function tests or cause severe hepatic toxicity as measured by lipid peroxidation and apoptosis markers such as malondialdehyde, Bax, and Bcl-2. However, PM-treated rats demonstrated a significant increase in hepatic glutathione, cytosolic superoxide dismutase (Cu/ZnSOD), tumor necrosis factor {alpha} mRNA expression, and cytochrome P450 (CYP) 2E1 and 1A2, suggesting adaptation to oxidative stress and possible drug-drug interactions.

Key Words: kava; pipermethystine; kavalactones; oxidative stress; cytochrome P450.


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