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Identification of novel electrophilic metabolites of piper methysticum Forst (Kava).
Chem Res Toxicol. 2003 Jun; 16(6):733-40.CR

Abstract

Dietary supplements containing Piper methysticum Forst. (kava) have been implicated in multiple cases of liver injury in humans, including 10 recently reviewed cases in which patients required liver transplantation following the usage of kava-containing products (Centers for Disease Control and Prevention, reprinted. (2003) J. Am. Med. Assoc. 289, 36-37). To investigate a possible mechanism(s) of kava-induced hepatotoxicity, an extract of kava was incubated in vitro with hepatic microsomes, NADPH, and GSH. Electrophilic intermediates that were generated via metabolic activation were trapped as GSH conjugates and removed from the protein mixture using ultrafiltration. Positive ion electrospray LC-MS/MS with precursor ion scanning was used for the selective detection of GSH conjugates, and LC-MS(n) product ion scanning was used to elucidate their structures. Using this in vitro MS-based screening assay, two novel electrophilic metabolites of kava, 11,12-dihydroxy-7,8-dihydrokavain-o-quinone and 11,12-dihydroxykavain-o-quinone, were identified. Mercapturic acids of these quinoid species were not detected in the urine of a human volunteer following ingestion of a dietary supplement that contained kava; instead, the corresponding catechols were metabolized extensively to glucuronic acid and sulfate conjugates. These observations indicate that quinoid metabolites, under most circumstances, are probably not formed in substantial quantities following the ingestion of moderate doses of kava. However, the formation of electrophilic quinoid metabolites by hepatic microsomes in vitro suggests that such metabolites might contribute to hepatotoxicity in humans when metabolic pathways are altered (e.g., because of a drug interaction, genetic difference in enzyme expression, etc.) or if conjugation pathways become saturated.

Authors+Show Affiliations

Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12807356

Citation

Johnson, Benjamin M., et al. "Identification of Novel Electrophilic Metabolites of Piper Methysticum Forst (Kava)." Chemical Research in Toxicology, vol. 16, no. 6, 2003, pp. 733-40.
Johnson BM, Qiu SX, Zhang S, et al. Identification of novel electrophilic metabolites of piper methysticum Forst (Kava). Chem Res Toxicol. 2003;16(6):733-40.
Johnson, B. M., Qiu, S. X., Zhang, S., Zhang, F., Burdette, J. E., Yu, L., Bolton, J. L., & van Breemen, R. B. (2003). Identification of novel electrophilic metabolites of piper methysticum Forst (Kava). Chemical Research in Toxicology, 16(6), 733-40.
Johnson BM, et al. Identification of Novel Electrophilic Metabolites of Piper Methysticum Forst (Kava). Chem Res Toxicol. 2003;16(6):733-40. PubMed PMID: 12807356.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of novel electrophilic metabolites of piper methysticum Forst (Kava). AU - Johnson,Benjamin M, AU - Qiu,Sheng-Xiang, AU - Zhang,Shide, AU - Zhang,Fagen, AU - Burdette,Joanna E, AU - Yu,Linning, AU - Bolton,Judy L, AU - van Breemen,Richard B, PY - 2003/6/17/pubmed PY - 2004/2/5/medline PY - 2003/6/17/entrez SP - 733 EP - 40 JF - Chemical research in toxicology JO - Chem Res Toxicol VL - 16 IS - 6 N2 - Dietary supplements containing Piper methysticum Forst. (kava) have been implicated in multiple cases of liver injury in humans, including 10 recently reviewed cases in which patients required liver transplantation following the usage of kava-containing products (Centers for Disease Control and Prevention, reprinted. (2003) J. Am. Med. Assoc. 289, 36-37). To investigate a possible mechanism(s) of kava-induced hepatotoxicity, an extract of kava was incubated in vitro with hepatic microsomes, NADPH, and GSH. Electrophilic intermediates that were generated via metabolic activation were trapped as GSH conjugates and removed from the protein mixture using ultrafiltration. Positive ion electrospray LC-MS/MS with precursor ion scanning was used for the selective detection of GSH conjugates, and LC-MS(n) product ion scanning was used to elucidate their structures. Using this in vitro MS-based screening assay, two novel electrophilic metabolites of kava, 11,12-dihydroxy-7,8-dihydrokavain-o-quinone and 11,12-dihydroxykavain-o-quinone, were identified. Mercapturic acids of these quinoid species were not detected in the urine of a human volunteer following ingestion of a dietary supplement that contained kava; instead, the corresponding catechols were metabolized extensively to glucuronic acid and sulfate conjugates. These observations indicate that quinoid metabolites, under most circumstances, are probably not formed in substantial quantities following the ingestion of moderate doses of kava. However, the formation of electrophilic quinoid metabolites by hepatic microsomes in vitro suggests that such metabolites might contribute to hepatotoxicity in humans when metabolic pathways are altered (e.g., because of a drug interaction, genetic difference in enzyme expression, etc.) or if conjugation pathways become saturated. SN - 0893-228X UR - https://www.unboundmedicine.com/medline/citation/12807356/Identification_of_novel_electrophilic_metabolites_of_piper_methysticum_Forst__Kava__ L2 - https://doi.org/10.1021/tx020113r DB - PRIME DP - Unbound Medicine ER -