title: In vitro genotoxicity of danthron and its potential mechanism.
abstract: To ascertain the in vitro genotoxicity of danthron and its potential mechanism of action, we performed an Ames test, a cytokinesis-block micronucleus assay and a comet assay in Balb/c 3T3 cells. The Ames test revealed that danthron was mutagenic only toward Salmonella typhimurium strain TA102 in the presence of an exogenous metabolic activation system (S9 mix). Danthron (25, 50 and 100μg/ml) increased the frequencies of micronuclear cells with or without S9 mix, and the comet length, tail length and Olive tail moment in comet assays without S9 mix in a dose-dependent manner. These results demonstrated the in vitro genotoxicity of danthron and that 3T3 cells are capable of activating danthron. When NADP was replaced by NAD in the S9 mix, danthron remained mutagenic toward strain TA102. The addition of dicoumarol, a DT-diaphorase inhibitor, decreased the number of danthron-induced histidine revertants by 35-39%, indicating that DT-diaphorase is involved in the metabolic activation of danthron in the presence of NADH as an electron donor. In 3T3 cells, increases in reactive oxygen species (ROS) formation and 8-hydroxydeoxyguanosine levels as well as a reduction in GSH levels were induced by danthron in a dose-dependent manner, indicating that oxidative stress may be a major contributing pathway in the genotoxicity of danthron.
authors.affiliation: Department of Toxicology, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zhang
authors.forename: Juanling
authors.initials: J
authors.lastname: Fu
authors.forename: Biyun
authors.initials: B
authors.lastname: Yao
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Zhao
authors.forename: Zongcan
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000633:toxicity*; D041702:BALB 3T3 Cells; D001711:Biotransformation; D020552:Comet Assay; D001728:Dicumarol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009249:NADP / Q000737:chemistry; D018384:Oxidative Stress; D012486:Salmonella typhimurium / Q000235:genetics
chemical_list: D000880:Anthraquinones; D009153:Mutagens; D009249:NADP; D001728:Dicumarol; D016660:NAD(P)H Dehydrogenase (Quinone); C004315:danthron