PT  - JOURNAL ARTICLE
AU  - Wan Chan
AU  - Hai-Bin Luo
AU  - Yufang Zheng
AU  - Yuen-Kit Cheng
AU  - Zongwei Cai
TI  - Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats
AID  - 10.1124/dmd.106.013979
DP  - 2007 Jun 01
TA  - Drug Metabolism and Disposition
PG  - 866--874
VI  - 35
IP  - 6
4099  - http://dmd.aspetjournals.org/content/35/6/866.short
4100  - http://dmd.aspetjournals.org/content/35/6/866.full
SO  - Drug Metab Dispos2007 Jun 01; 35
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics