title: Comparison of the mutagenicity of aristolochic acid I and aristolochic acid II in the gpt delta transgenic mouse kidney.
abstract: Aristolochic acid (AA) is known to be a potent mutagen and carcinogen. Aristolochic acid I (AAI) and aristolochic acid II (AAII), the two major components of AA, differ from each other by a single methoxy group. However, their individual mutagenic characteristics in vivo are unclear. In the present study, we compared their DNA adduct formation and mutagenicities in the gpt delta transgenic mouse kidney. The dA-AAI, dG-AAI, dA-AAII and dG-AAII were identified in the kidney two days after intragastric administration of AAI or AAII at 5mg/kg. The concentration of DNA adducts formed by AAII was approximately 2.5-fold higher than that formed by AAI (p<0.05). The mutant frequency induced by AAII was nearly two-fold higher than that induced by AAI (p<0.05) following administration of 5mg/kg AAI or AAII, five times per week for six weeks. Investigation of the mutation spectra showed no statistically significant difference between AAI- and AAII-treated mice (p>0.05). A:T to T:A transversion was the predominant type of mutation in both treated groups, the GC-associated mutation rates, however, differed between the AAI and AAII treatments. The in vivo metabolic pathways of AAI and AAII are different, and this may affect their mutagenicity. In the present study, we measured the levels of AAI and AAII in the kidney and plasma of gpt delta transgenic mice at multiple time points after a single intragastric dose of 1 or 5mg/kg of either component. Our results showed that the levels of AAII in both kidney and plasma were considerably higher than those of AAI (p<0.01). The present study indicated that AAII showed more carcinogenic risk than AAI in vivo, and this may be, at least partly, the result of its increased levels in kidney and plasma.
authors.affiliation: Center for Drug Safety and Evaluation Research, State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Xing
authors.forename: Xinming
authors.initials: X
authors.lastname: Qi
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Yuanfeng
authors.initials: Y
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Likun
authors.initials: L
authors.lastname: Gong
authors.forename: Takehiko
authors.initials: T
authors.lastname: Nohmi
authors.forename: Yang
authors.initials: Y
authors.lastname: Luan
authors.forename: Jin
authors.initials: J
authors.lastname: Ren
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000493:pharmacokinetics / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D018736:DNA Adducts; D004249:DNA Damage; D029968:Escherichia coli Proteins / Q000235:genetics*; D007668:Kidney / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D009153:Mutagens / Q000633:toxicity*; D010430:Pentosyltransferases / Q000235:genetics*
chemical_list: D034341:Aristolochic Acids; D002273:Carcinogens; D018736:DNA Adducts; D029968:Escherichia coli Proteins; D009153:Mutagens; C000228:aristolochic acid I; C042310:aristolochic acid II; D010430:Pentosyltransferases; C071962:Gpt protein, E coli