title: Application of simplified in vitro screening tests to detect genotoxicity of aristolochic acid.
abstract: Aristolochic acid (AA), the active compound found in Aristolochia extracts, has been used as a traditional medicine. However, products containing AA were withdrawn from the market in the early 1980s because AA was found to be a potent carcinogen. Some genotoxicity studies of AA were conducted after the carcinogenicity of AA was reported. The purpose of this study was to check the ability of simplified, screening tests for genotoxicity to indicate the genotoxic activities of AA. Four commonly used in vitro genotoxicity endpoints were examined. In a bacterial mutation screening test, AA was mutagenic to tester strains TA98 and TA100 with and without rat liver S9. In the L5178Y mouse lymphoma cell gene mutation test, mutagenic activity was observed at > or = 25 microg/ml with or without S9. A concentration-dependent increase in structural chromosome aberrations was observed in CHO cells, with significant increases at 50 microg/ml without S9 and at 25 microg/ml with S9. Significant increases in micronucleated binucleated cells were observed in CHO cells treated with AA at > or = 25 microg/ml with or without S9. These results demonstrated that the genotoxicity of AA would have been easily detected if simple screening versions of in vitro genotoxicity assays had been used during early product development. It is suggested that simplified screening tests such as those used in this study would be a rapid and economical way of obtaining the preliminary genotoxicity profiles of new substances or products as an aid to decision-making for further development.
authors.affiliation: Covance Laboratories Inc., Vienna, VA 22182, USA. hzhang@rdg.boehringer-ingelheim.com
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: M A
authors.initials: MA
authors.lastname: Cifone
authors.forename: H
authors.initials: H
authors.lastname: Murli
authors.forename: G L
authors.initials: GL
authors.lastname: Erexson
authors.forename: M S
authors.initials: MS
authors.lastname: Mecchi
authors.forename: T E
authors.initials: TE
authors.lastname: Lawlor
mesh_terms: D000818:Animals; D034341:Aristolochic Acids / Q000633:toxicity*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations / Q000187:drug effects; D006224:Cricetinae; D003470:Culture Media; D006639:Histidine / Q000378:metabolism; D066298:In Vitro Techniques; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D015162:Micronucleus Tests; D008862:Microsomes, Liver / Q000201:enzymology; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000633:toxicity*; D010936:Plant Extracts / Q000633:toxicity; D051381:Rats; D012486:Salmonella typhimurium / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D003470:Culture Media; D009153:Mutagens; D010936:Plant Extracts; D006639:Histidine; C000228:aristolochic acid I