title: The genotoxicity profile of atorvastatin, a new drug in the treatment of hypercholesterolemia.
abstract: While HMG-CoA reductase inhibitors such as fluvastatin, lovastatin, pravastatin and simvastatin demonstrate lack of in vitro and in vivo mutagenicity and clastogenicity in bacterial and mammalian cells, long term rodent carcinogenicity studies resulted in an increased incidence in neoplasms at high doses. These effects may be attributable to an exaggeration of the desired biochemical effect of the drug and/or a tumor promoting effect. The genotoxicity of atorvastatin, a newly developed HMG-CoA reductase inhibitor, was evaluated in a variety of test systems. In bacterial mutagenicity tests, the E. coli tester strain WP2(uvrA) and S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 were exposed to concentrations of atorvastatin as high as 5000 micrograms/plate both in the absence (S9-) and presence (S9+) of metabolic activation. Atorvastatin was not mutagenic in either E. coli or S. typhimurium. Chinese hamster lung V79 cell cultures were exposed to atorvastatin at concentrations of 50-300 micrograms/ml (S9-) and 100-300 micrograms/ml (S9+) and structural chromosome aberrations were assessed. Mutation at the hgprt locus was assessed at concentrations of 100-300 micrograms/ml (S9-) and 150-275 micrograms/ml (S9+). Atorvastatin was neither mutagenic nor clastogenic in the absence or presence of S9. The lack of in vitro genotoxicity was corroborated in vivo in a mouse micronucleus study in which single oral doses of atorvastatin were administered to male and female CD-1 mice at 1, 2500, or 5000 mg/kg. No biologically significant increases in the frequency of micronucleated polychromatic erythrocytes in bone marrow at 24, 48, or 72 h postdosing were observed. Thus, atorvastatin, as with the other tested HMG-CoA reductase inhibitors, is not genotoxic.
authors.affiliation: Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ciaravino
authors.forename: M L
authors.initials: ML
authors.lastname: Kropko
authors.forename: C E
authors.initials: CE
authors.lastname: Rothwell
authors.forename: C A
authors.initials: CA
authors.lastname: Hovey
authors.forename: J C
authors.initials: JC
authors.lastname: Theiss
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000633:toxicity*; D000069059:Atorvastatin; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects; D006538:Heptanoic Acids / Q000633:toxicity*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006937:Hypercholesterolemia / Q000188:drug therapy; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008168:Lung; D008297:Male; D051379:Mice; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D011758:Pyrroles / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
chemical_list: D000924:Anticholesteremic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin; D007041:Hypoxanthine Phosphoribosyltransferase