Linked Life Data

11095586

Source:http://linkedlifedata.com/resource/pubmed/id/11095586

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2001-2-2
pubmed:abstractText
The metabolism of the hepatotoxic otonecine-type pyrrolizidine alkaloid (PA), clivorine, was investigated using rat liver microsomes. The metabolites dehydroretronecine (DHR), 7-glutathionyldehydroretronecine (7-GSH-DHR), 7, 9-diglutathionyldehydroretronecine (7,9-diGSH-DHR), and clivoric acid were identified using chromatographic and mass spectrometric analyses. NMR characterizations were also performed on the isolated clivoric acid and the synthetic 7-GSH-DHR and 7,9-diGSH-DHR. The results indicated that the two glutathione (GSH) conjugates were formed by reaction of the unstable toxic pyrrolic ester with GSH added in the microsomal incubation system, whereas DHR was generated from hydrolysis of the unstable pyrrolic ester, and that clivoric acid was produced from all these further conversions of the unstable pyrrolic ester. Furthermore, tissue-bound pyrroles were also determined to be present after microsomal incubation of clivorine. Clivoric acid has not been previously identified, and DHR and 7, 9-diGSH-DHR were found, for the first time, as metabolites of an otonecine-type PA, while 7-GSH-DHR was previously reported by us to be a microsomal metabolite of clivorine. The in vitro metabolic pathway of clivorine was delineated to be the initial formation of the unstable pyrrolic ester, which then may undergo hydrolysis, GSH conjugations, or covalent binding with hepatic tissues that may lead to hepatotoxicity. The present definitive identification of four pyrrolic ester-related metabolites of clivorine and indirect determination of bound pyrroles provide the strongest evidence to date to support the hypothesis that the formation of an unstable pyrrolic ester plays a key role in otonecine-type PA-induced hepatotoxicity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
28
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1475-83
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2000
pubmed:articleTitle
Characterization of rat liver microsomal metabolites of clivorine, an hepatotoxic otonecine-type pyrrolizidine alkaloid.
pubmed:affiliation
Department of Pharmacology, The Chinese University of Hong Kong, Shantin, Hong Kong, Special Administrative Region of the People's Republic of China. linge@cuhk.edu.hk
pubmed:publicationType
Journal Article, In Vitro, Research Support, Non-U.S. Gov't