A comparison of the toxic and SCE-inducing effects of inhibitors of ADP-ribosyl transferase in Chinese hamster ovary cells.
The effects of inhibitors of ADP-ribosyl transferase (ADPRT), an enzyme believed to function in the maintenance of normal cellular functions, on specific genotoxic endpoints were examined in Chinese hamster ovary cells. Two classes of inhibitors, which differed both in their mechanism and efficiency of inhibition, were compared. Each of the inhibitors was found to increase the sister-chromatid exchange (SCE) frequency, reduce cloning efficiency, slow cell growth and potentiate methyl nitrosourea (MNU)-induced toxicity. With nicotinamide and two of its analogs, the relative ability to induce genotoxic endpoints generally followed the reported level of enzymatic inhibition. That is, benzamide was the most effective at inducing SCE and reducing cell survival and growth measurements, followed by nicotinamide and 1-methyl nicotinamide. However, no single quantitative relationship was found between the SCE and reduced cell survival caused by these agents. Theophylline, a representative methylxanthine, was the most toxic on the basis of concentration, but less effective than benzamide at inducing SCE. A strong association was found between the ability of the inhibitors to reduce cell survival, affect cell growth and potentiate the toxic effects of MNU. Therefore, although no consistent quantitative relationship could be demonstrated between SCE induction and the other endpoints for all ADPRT inhibitors, a general relationship was found between the toxic properties of nicotinamide and its analogs and their ability to induce SCE.
D000246:Adenosine Diphosphate Ribose / Q000502:physiology*; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D001549:Benzamides / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003434:Crossing Over, Genetic / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D009536:Niacinamide / Q000494:pharmacology; D009702:Nucleoside Diphosphate Sugars / Q000502:physiology*; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D011065:Poly(ADP-ribose) Polymerases; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D013806:Theophylline / Q000494:pharmacology
D000477:Alkylating Agents; D001549:Benzamides; D009702:Nucleoside Diphosphate Sugars; D000246:Adenosine Diphosphate Ribose; D009536:Niacinamide; C037689:benzamide; D013806:Theophylline; D011065:Poly(ADP-ribose) Polymerases; D009713:Nucleotidyltransferases