RT Journal Article
SR Electronic
T1 Investigation of the Metabolism and Reductive Activation of Carcinogenic Aristolochic Acids in Rats
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 866
OP 874
DO 10.1124/dmd.106.013979
VO 35
IS 6
A1 Wan Chan
A1 Hai-Bin Luo
A1 Yufang Zheng
A1 Yuen-Kit Cheng
A1 Zongwei Cai
YR 2007
UL http://dmd.aspetjournals.org/content/35/6/866.abstract
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