Promoting effects of kojic acid due to serum TSH elevation resulting from reduced serum thyroid hormone levels on development of thyroid proliferative lesions in rats initiated with N-bis(2-hydroxypropyl)nitrosamine

In order to examine whether kojic acid (KA) exerts a promoting effect on th yroid carcinogenesis, male F344 rats were initiated with N-bis(2-hydroxypro pyl)nitrosamine (BHP; 2800 mg/kg body wt, single s.c. injection) and, start ing 1 week later, received pulverized basal diet containing 2 or 0% KA for 12 weeks. Untreated control rats were given basal diet for 13 weeks. As an additional experiment, two groups without BHP initiation received basal die t or diet containing 2% KA for 20 weeks. The serum triiodothyronine (T3) an d thyroxine (T4) levels were significantly decreased (half to one-third of values of the BHP alone group) and serum thyroid-stimulating hormone (TSH) was markedly increased (13-19 times higher than the values of the BHP-alone group) in the BHP + KA group at weeks 4 and 12, Similar changes in serum t hyroid-related hormones were observed in the group with 2% KA alone at week 4, but not at week 20. Thyroid weights were significantly increased in the BHP + KA and KA-alone groups. Focal thyroid follicular hyperplasias and ad enomas were observed in 4/5 and 3/5 rats in the BHP + KA group at week 4, r espectively. At weeks 12, these lesions were observed in all rats in the BH P + KA group. Animals of the KA alone group showed marked diffuse hypertrop hy of follicular epithelial cells at weeks 4 and 20. No changes in thyroid- related hormone levels or thyroid histopathological lesions were observed i n either the BHP alone or the untreated control groups. Measurement of live r T4-uridine diphosphate glucuronosyltransferase (UDP-GT) activity at week 4 revealed no significant intergroup differences. These results suggest tha t thyroid proliferative lesions were induced by KA administration due to co ntinuous serum TSH stimulation through the negative feedback mechanism of t he pituitary-thyroid axis, with decreases of T3 and T4 caused by a mechanis m independent of T4-UDP-GT activity.