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Study of the phase I and phase II metabolism of nephrotoxin aristolochic acid by liquid chromatography/tandem mass spectrometry
Author(s) -
Chan Wan,
Cui Liang,
Xu Guowang,
Cai Zongwei
Publication year - 2006
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.2513
Subject(s) - chemistry , aristolochic acid , chromatography , carcinogen , metabolic pathway , glucuronidation , tandem mass spectrometry , hydroxylation , metabolism , urine , mass spectrometry , liquid chromatography–mass spectrometry , in vivo , microsome , biochemistry , enzyme , microbiology and biotechnology , biology , genetics
Prolonged exposure to aristolochic acid (AA) was shown to pose rapid progressive renal fibrosis in Belgian women in a slimming regime in the early 1990s. AA was also demonstrated to be strong carcinogen in rats. The carcinogenicity of AA is generally believed to be related to the nitro‐reduction of AA, in which the aristolactam‐nitriumion ion with a delocalized positive charge is the ultimate carcinogen. In this study, the phase I and phase II metabolism of AA was investigated by using an in vitro system with rat liver S9 and an in vivo animal study with Sprague‐Dawley rats. AA was found to have been undergone hydroxylation, lactam formation, and desnitro and desmethyl transformations. Three conjugated metabolites of AA, namely the N ‐ and O ‐glucuronides of aristolactams, were detected directly in pre‐concentrated urine sample, with no acid hydrolysis or enzymatic digestion. Structural elucidation of the metabolites was performed by using liquid chromatography/tandem mass spectrometry (LC/MS/MS). The results indicated that N‐glucuronidation was the major phase II metabolic pathway for the aristolactams formed by AA after their nitro‐reduction. Copyright © 2006 John Wiley & Sons, Ltd.