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Protective Effects of Thymidine, 5-Aminoimidazolecarboxamide, and Riboflavin against Fetal Abnormalities Produced in Rats by 5-(3,3-Dimethyl-1-triazeno)imidazole-4-carboxamide¹

Institute of Rehabilitation Medicine, New York University Medical Center, New York, New York 10016

Single doses of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DIC), 200 to 1000 or 25 to 1000 mg/kg, injected i.p. into rats on the 11th or 12th day of pregnancy, respectively, produced dose-related malformations of the mandible, palate, brain, and limbs of fetuses examined on the 21st day of gestation. Doses of 200 to 1000 mg/kg injected on Days 9 or 10 were lethal but not teratogenic.

Similarly, 5 - [3,3 - bis(2 - chlorethyl) - 1 - triazeno]imidazole-4-carboxamide and dimethylnitrosoamine injected on Day 12 at dosages of 100 to 800 and 5 to 40 mg/kg, respectively, were lethal but not teratogenic. The maternal toxicity of dimethylnitrosoamine was about 6.5 times greater than that of 5-[3,3-bis(2-chlorethyl)-1-triazeno]imidazole-4-carboxamide and 10 times greater than that of DIC, while its lethal effect on the fetus was 10 and 20 times greater than that of 5-[3,3-bis(2-chloroethyl)-1-triazeno]imidazole-4-carboxamide and DIC, respectively.

Injections i.p. (on a mg/kg basis of maternal body weight) of thymidine (25 to 1000 mg), 5-aminoimidazolecarboxamide (AIC; 50 to 800 mg), riboflavin (10 to 20 mg), and DL-cysteine (200 to 400 mg) into 12th-day pregnant rats were neither toxic nor teratogenic. When these doses were given simultaneously (0 time) with 400 mg of DIC per kg, varying degrees of protection (increased number of normal fetuses at Day 21) against DIC-induced teratogenicity were observed. Thus 50 to 1000 mg of thymidine per kg gave from 54 to 78% protection, and 200 and 400 mg of AIC per kg gave from 9 to 26% protection. Combinations of riboflavin and cysteine (doses of 20 and 400 and of 10 and 200 mg/kg, respectively) provided from 2.7 to 4.9% (p < 0.001) protection, while 800 mg of AIC or 400 mg of cysteine per kg alone with DIC did not protect.

When thymidine (200 mg/kg) was given at varying time intervals (15 to 30 min) before or after DIC treatment (400 mg/kg), its protectivity declined with pre- or posttreatment time. On the other hand, pretreatment (30 min) with AIC (400 mg/kg) provided protection equivalent to that seen when the same amount of this compound was given at 0 time.

Pretreatment (30 min) with cysteine (400 mg/kg) gave no protection against DIC-induced (400 mg/kg) malformations.

¹ This work was supported in part by the Social and Rehabilitation Service, Department of Health, Education and Welfare, under the designation of New York University as a Rehabilitation Research and Training Center (RT-1), and by a grant from the Foundation for Child Development, New York, N. Y. 10017.

Received 12/20/72. Accepted 6/ 5/73.