Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice.
A previous study demonstrated that caffeine strongly potentiated the teratogenic action of mitomycin C in mice. In the present study the effect of methylxanthines including caffeine, theophylline, theobromine (theobromine sodium salicylate), paraxanthine, and 1-methylxanthine was compared in order to analyze the structure-activity relationship. Jcl:ICR mice were injected IP with 3 mg/kg of mitomycin C, immediately followed by SC injection of each methylxanthine on day 11 of gestation. The doses of methylxanthines were calculated so that the mice received 50 mg/kg of caffeine or the equimolecular amount of the other methylxanthines. Fetuses were examined for external malformations on day 18 of gestation. Mitomycin C at 3 mg/kg and the methylxanthines at the doses used were not teratogenic. Combined administration of caffeine or theophylline with mitomycin C produced more than 80% of malformed fetuses. Although less effective than caffeine or theophylline, paraxanthine also significantly increased the incidence of malformed fetuses. Theobromine and 1-methylxanthine were virtually ineffective. From these findings, it is suggested that the methyl group at N-1 position of the xanthines is important for the enhancement but the N-1 methylation alone is ineffective unless accompanied with the substitution of the methyl moiety at the other position(s).
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D002110:Caffeine / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D016685:Mitomycin; D008937:Mitomycins / Q000633:toxicity*; D011247:Pregnancy; D013329:Structure-Activity Relationship; D013805:Theobromine / Q000633:toxicity; D013806:Theophylline / Q000633:toxicity; D014970:Xanthines / Q000633:toxicity*
D000903:Antibiotics, Antineoplastic; D008937:Mitomycins; D014970:Xanthines; C008514:methylxanthine; D002110:Caffeine; D016685:Mitomycin; D013806:Theophylline; D013805:Theobromine; C021183:1,7-dimethylxanthine