Studies on the mode of action for thyroid gland tumor promotion in rats by phenobarbital

A study was conducted to determine the mode of action for phenobarbital promotion of thyroid follicular cell neoplasia in rats using an initiation-promotion model established by Hiasa et al. (Y. Hiasa, Y. Kitahori, M. Ohshima, T. Fujita, T. Yuasa, N. Konishi, and A. Miyashiro, 1982a, Carcinogenesis 3, 1187-1190). Seven groups of Charles River Crl: CD(SD)BR rats (20/sex/group) were treated with either saline or 700 mg/kg DHPN [N-bis(2-hydroxypropyl)nitrosamine] administered subcutaneously once a week for 5 weeks (Initiation Phase) followed by 15 weeks of treatment with control diet or diets containing 500 ppm of phenobarbital (Promotion Phase). Groups of rats were also treated with L-thyroxine (50 micrograms/kg/day) in the diet to determine its effect on thyroid gland tumor promotion by phenobarbital. The incidence of thyroid follicular adenomas in DHPN male rats treated with phenobarbital was markedly increased [83% (15/18 rats)] as compared to rats receiving DHPN alone [37% (6/16 rats)]. Thyroxine treatment completely blocked the tumor promoting effect of phenobarbital in that the tumor incidence [25% (5/20 rats)] was reduced back to or somewhat less than that observed with DHPN alone. In female rats no tumors were observed with DHPN nor was a promoting effect of phenobarbital observed. These results demonstrate the potential for a microsomal enzyme inducer such as phenobarbital to alter the incidence of thyroid gland neoplasia in the male rat. The inhibitory effect of L-thyroxine on tumor promotion by phenobarbital supports the hypothesis that the promoting effect of phenobarbital is mediated via increased pituitary secretion of thyroid stimulating hormone as a compensatory response to the known effects of phenobarbital on peripheral thyroxine metabolism and excretion.