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High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats.
Food Chem Toxicol. 2008 Dec; 46(12):3732-8.FC

Abstract

Commercial products containing the kava plant (Piper methysticum), known to have the anxiolytic activity, are banned in several European countries and Canada because of the suspicion of a potential liver toxicity. In some reports, kava and kavalactones (major constituents of kava) inhibited activities of cytochrome P450 (CYP) isoforms including CYP1A2. On the other hand, a few studies showed that administration of kava to rats moderately increased CYP1A2 proteins in the liver. CYP1A isoforms are likely responsible for the metabolic activation of potent carcinogenic environmental toxins such as aflatoxins, benzo[a]pyrene, and others. On these bases, we have investigated the effects of administration of commercial kava products on gene expression of hepatic CYP1A isoforms in rats. A high dose (equivalent to approximately 380mg kavalactones/kg/day; 100 times of the suggested dosage for human use) of two different types of kava products for 8 days significantly increased liver weights. CYP1A2 mRNA expression was moderately increased (2.8-7.3 fold). More importantly, the high dose of kava markedly enhanced CYP1A1 mRNA expression (75-220 fold) as well as ethoxyresorufin O-deethylase activities and CYP1A1 immunoreactivities. Thus, no observed adverse effect levels of kavalactones would be lower than 380mg/kg/day. When the safety factor of kavalactones is assumed to be 100, a value most often used upon the risk analysis of chemicals and designed to account for interspecies and intraspecies variations, a number of kava product users likely ingest more kavalactones than acceptable daily intakes. Based on overall evidence, we should pay considerable attention to the possibility that kava products induce hepatic CYP1A1 expression in human especially in sensitive individuals.

Authors+Show Affiliations

Department of Food and Nutritional Sciences, Jumonji University, 2-1-28 Sugasawa, Niiza, Saitama 352-8510, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18930106

Citation

Yamazaki, Yuko, et al. "High Dose of Commercial Products of Kava (Piper Methysticum) Markedly Enhanced Hepatic Cytochrome P450 1A1 mRNA Expression With Liver Enlargement in Rats." Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, vol. 46, no. 12, 2008, pp. 3732-8.
Yamazaki Y, Hashida H, Arita A, et al. High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats. Food Chem Toxicol. 2008;46(12):3732-8.
Yamazaki, Y., Hashida, H., Arita, A., Hamaguchi, K., & Shimura, F. (2008). High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats. Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, 46(12), 3732-8. https://doi.org/10.1016/j.fct.2008.09.052
Yamazaki Y, et al. High Dose of Commercial Products of Kava (Piper Methysticum) Markedly Enhanced Hepatic Cytochrome P450 1A1 mRNA Expression With Liver Enlargement in Rats. Food Chem Toxicol. 2008;46(12):3732-8. PubMed PMID: 18930106.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High dose of commercial products of kava (Piper methysticum) markedly enhanced hepatic cytochrome P450 1A1 mRNA expression with liver enlargement in rats. AU - Yamazaki,Yuko, AU - Hashida,Hiroko, AU - Arita,Anna, AU - Hamaguchi,Keiko, AU - Shimura,Fumio, Y1 - 2008/09/30/ PY - 2008/06/10/received PY - 2008/08/27/revised PY - 2008/09/22/accepted PY - 2008/10/22/pubmed PY - 2009/1/27/medline PY - 2008/10/22/entrez SP - 3732 EP - 8 JF - Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association JO - Food Chem Toxicol VL - 46 IS - 12 N2 - Commercial products containing the kava plant (Piper methysticum), known to have the anxiolytic activity, are banned in several European countries and Canada because of the suspicion of a potential liver toxicity. In some reports, kava and kavalactones (major constituents of kava) inhibited activities of cytochrome P450 (CYP) isoforms including CYP1A2. On the other hand, a few studies showed that administration of kava to rats moderately increased CYP1A2 proteins in the liver. CYP1A isoforms are likely responsible for the metabolic activation of potent carcinogenic environmental toxins such as aflatoxins, benzo[a]pyrene, and others. On these bases, we have investigated the effects of administration of commercial kava products on gene expression of hepatic CYP1A isoforms in rats. A high dose (equivalent to approximately 380mg kavalactones/kg/day; 100 times of the suggested dosage for human use) of two different types of kava products for 8 days significantly increased liver weights. CYP1A2 mRNA expression was moderately increased (2.8-7.3 fold). More importantly, the high dose of kava markedly enhanced CYP1A1 mRNA expression (75-220 fold) as well as ethoxyresorufin O-deethylase activities and CYP1A1 immunoreactivities. Thus, no observed adverse effect levels of kavalactones would be lower than 380mg/kg/day. When the safety factor of kavalactones is assumed to be 100, a value most often used upon the risk analysis of chemicals and designed to account for interspecies and intraspecies variations, a number of kava product users likely ingest more kavalactones than acceptable daily intakes. Based on overall evidence, we should pay considerable attention to the possibility that kava products induce hepatic CYP1A1 expression in human especially in sensitive individuals. SN - 0278-6915 UR - https://www.unboundmedicine.com/medline/citation/18930106/High_dose_of_commercial_products_of_kava__Piper_methysticum__markedly_enhanced_hepatic_cytochrome_P450_1A1_mRNA_expression_with_liver_enlargement_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-6915(08)00551-6 DB - PRIME DP - Unbound Medicine ER -