Investigation of the metabolism and reductive activation of carcinogenic aristolochic acids in rats

Wan Chan, Hai Bin Luo, Yufang Zheng, Yuen Kit CHENG, Zongwei CAI*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

57 Citations (Scopus)

Abstract

The metabolic activation of aristolochic acids (AAs) that have been demonstrated to be mutagenic and carcinogenic was investigated. In vitro metabolism study indicated that AAs were metabolized to N-hydroxyaristolactam, which could be either reduced to aristolactams or rearranged to 7-hydroxyaristolactams via the Bamberger rearrangement. In vivo metabolism study is important because the intermediates (aristolactam-nitriumion) of the nitroreduction process are thought to be responsible for the carcinogenicity of AAs. Liquid chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (MS/MS) were applied to the analyses of a series of positional isomers of hydroxyaristolactams in rat urine samples after the in vivo study of AAs. Three hydroxylated metabolites of aristolactam II and two hydroxylated metabolites of aristolactam I were identified. The structures of the positional isomers were elucidated from the interpretation of MS/MS spectra and theoretical calculations. In addition, several new metabolites were detected in the rat urine by high-resolution mass spectrometry and MS/MS, including those from the decarboxylation of AAs and the conjugations of acetylation, glucuronidation, and sulfation of aristolochic acid Ia.

Original languageEnglish
Pages (from-to)866-874
Number of pages9
JournalDrug Metabolism and Disposition
Volume35
Issue number6
DOIs
Publication statusPublished - Jun 2007

Scopus Subject Areas

  • Pharmacology
  • Pharmaceutical Science

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