Genetic toxicity of cocaine.
Cocaine is a widely abused drug. Recently, it has been shown to induce teratogenesis in both humans and animals. Cocaine-induced teratogenicity has been associated with reactive oxygen species (ROS), which are generated by cytochrome P450 during cocaine biotransformation. Since ROS have been reported to induce genotoxicity, it is of interest to know whether cocaine and/or its metabolites are also genotoxic. In this study, Chinese hamster ovary K1 cells were employed as a model system to investigate the genetic toxicity of cocaine in the presence or absence of rat liver S9 fraction. Cocaine-induced cytotoxicity was potentiated when S9 was present, indicating the cytochrome P450 metabolism plays a role in cocaine-mediated cytotoxicity. Cocaine treatments per se induced a few chromosome aberrations while treatments of cocaine plus S9 caused a significant increase in chromosome aberrations. In contrast, cocaine induced micronuclei (MN) formation and hypoxanthine-guanine phosphoribosyltransferase mutation only in the presence of S9. Therefore, cocaine itself is at best a weak clastogen, whereas metabolite(s) of cocaine is/are truly inducer(s) of clastogenesis and mutagenesis. Cocaine treatments alone also induced a significant increase in sister chromatid exchange frequency but the addition of S9 did not affect the results. Free radical scavengers, including superoxide dismutase and catalase, efficiently decreased the frequency of cocaine plus S9-induced MN, implying that ROS are indeed important components in cocaine-induced genotoxicity. The observation that non-toxic doses of cocaine can inhibit intercellular metabolic cooperation suggests that cocaine may also be a tumor promoter. Our data supports that cocaine could possess genotoxicity in addition to its well-known neurotoxicity and teratogenicity.
Yu
R C
RC
Institute of Genetics, National Yang-Ming University, Taipei, Taiwan.
Lee
T C
TC
Wang
T C
TC
Li
J H
JH
D000818:Animals; D016466:CHO Cells; D002374:Catalase / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002869:Chromosome Aberrations; D003042:Cocaine / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008099:Liver / Q000201:enzymology; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000502:physiology*; D012854:Sister Chromatid Exchange / Q000187:drug effects; D013482:Superoxide Dismutase / Q000494:pharmacology
D017382:Reactive Oxygen Species; D003577:Cytochrome P-450 Enzyme System; D002374:Catalase; D013482:Superoxide Dismutase; D007041:Hypoxanthine Phosphoribosyltransferase; D003042:Cocaine