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Identification of Novel Electrophilic Metabolites of Piper methysticum Forst. (Kava)
- Source :
- Chemical Research in Toxicology. 16:733-740
- Publication Year :
- 2003
- Publisher :
- American Chemical Society (ACS), 2003.
-
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.
- Subjects :
- Adult
Male
Spectrometry, Mass, Electrospray Ionization
Toxicology
Rats, Sprague-Dawley
chemistry.chemical_compound
medicine
Animals
Humans
Kava
Liver injury
chemistry.chemical_classification
Plant Extracts
Piper methysticum
General Medicine
Glutathione
Glucuronic acid
medicine.disease
Acetylcysteine
Rats
Metabolic pathway
Enzyme
chemistry
Biochemistry
Dietary Supplements
Microsomes, Liver
Microsome
Subjects
Details
- ISSN :
- 15205010 and 0893228X
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- Chemical Research in Toxicology
- Accession number :
- edsair.doi.dedup.....dd741922030eb2d21570cbceaf5dfdd4