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Research ArticleArticle

Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats

Wan Chan, Hai-Bin Luo, Yufang Zheng, Yuen-Kit Cheng and Zongwei Cai
Drug Metabolism and Disposition June 2007, 35 (6) 866-874; DOI: https://doi.org/10.1124/dmd.106.013979
Wan Chan
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Hai-Bin Luo
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Yufang Zheng
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Yuen-Kit Cheng
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Zongwei Cai
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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.

Footnotes

  • doi:10.1124/dmd.106.013979.

  • We thank the Faculty Research Grant of the Hong Kong Baptist University and the Research Grant Council, University Grants Committee of Hong Kong (HKBU2154/04M) for their financial support of this study.

  • ABBREVIATIONS: AA, aristolochic acid; AAIa, aristolochic acid Ia; SPE, solid-phase extraction; HPLC, high performance liquid chromatography; ESI-MS, electrospray ionization-mass spectrometry; LC-MS, liquid chromatography-mass spectrometry; MS/MS, tandem mass spectrometry; HR-MS, high-resolution mass spectrometry.

    • Received November 19, 2006.
    • Accepted March 6, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (6)
Drug Metabolism and Disposition
Vol. 35, Issue 6
1 Jun 2007
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Research ArticleArticle

Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats

Wan Chan, Hai-Bin Luo, Yufang Zheng, Yuen-Kit Cheng and Zongwei Cai
Drug Metabolism and Disposition June 1, 2007, 35 (6) 866-874; DOI: https://doi.org/10.1124/dmd.106.013979

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Research ArticleArticle

Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats

Wan Chan, Hai-Bin Luo, Yufang Zheng, Yuen-Kit Cheng and Zongwei Cai
Drug Metabolism and Disposition June 1, 2007, 35 (6) 866-874; DOI: https://doi.org/10.1124/dmd.106.013979
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