title: Inhibition of mouse testicular DNA synthesis by mutagens and carcinogens as a potential sample mammalian assay for mutagenesis.
abstract: Since mutagenic substances induce structural changes in DNA, studies were undertaken to determine whether substances would modify DNA replicative activity. DNA synthesis was quantitated 3.5 h after drug administration as uptake into DNA of a 30-min pulse of 10 muCi of [3H] thymidine. Combinations of methylurea (20000 mg/kg) and sodium nitrite (150 mg/kg) administered p.o. resulted in gastric synthesis of nitrosomethylurea and inhibited testicular DNA synthesis by 83%. Combinations of methylurea and sodium nitrite of 1000 and 100 mg/kg respectively inhibited DNA synthesis by 75%. With dimethylamine and sodium nitrite, a combination which results in gastric synthesis of dimethylnitrosamine, inhibitions of 65 and 57% were observed at 2000 mg/kg together with 150 mg/kg and 1000 mg/kg in combination with 100 mg/kg, respectively. In separate experiments, dimethylnitrosamine (50 mg/kg, p.o.) and diethylnitrosamine (100 mg/kg, i.p.) inhibited thymidine uptake by 30 and 89%, respectively. The mutagenic polynucelar hydrocarbon 3-methylcholanthrene (15 mg/kg) inhibited DNA synthesis by 95% and safrole (640 mg/kg), a mutagenic methylenedioxybenzene derivative, inhibited by 60%. Cadmium chloride (10 mg/kg), acetylaminofluorene (160 mg/kg) and dibutylnitrosamine (500 mg/kg) also induced statistically significant effects. Noncarcinogenic analogues of these substances (anthracene, 125 mg/kg; diphenyl-nitrosamine, 500 mg/kg; piperonyl butoxide, 640 mg/kg, and methylurea, 2000 mg/kg in combination with sodium nitrate) were inactive. Highly toxic substances (potassium cyanide, 2.5 mg/kg; 2,4-dinitrophenol, 20 mg/kg; and lead acetate, 150 mg/kg) were also inactive. This index of mutagenicity appears to have considerable sensitivity and therefore may have potential in drug evaluation.
mesh_terms: D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D004261:DNA Replication / Q000187:drug effects*; D004048:Diethylamines / Q000494:pharmacology; D008297:Male; D008782:Methylurea Compounds / Q000494:pharmacology; D051379:Mice; D009153:Mutagens / Q000494:pharmacology*; D009573:Nitrites / Q000494:pharmacology; D009602:Nitrosamines / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D012451:Safrole / Q000494:pharmacology; D013737:Testis / Q000187:drug effects* / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004048:Diethylamines; D008782:Methylurea Compounds; D009153:Mutagens; D009573:Nitrites; D009602:Nitrosamines; D009607:Nitrosourea Compounds; D002104:Cadmium; D012451:Safrole