TIME COURSE OBSERVATION OF THYROID PROLIFERATIVE LESIONS AND SERUM LEVELS OF RELATED HORMONES IN RATS TREATED WITH KOJIC ACID AFTER DHPN INITIATION

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Time course changes in thyroid proliferative lesions as well as related hormone levels in the blood of male F344 rats given N-bis (2-hydroxypropyl) nitrosamine (DHPN: 2800 mg/kg body weight, single s.c. injection) as an initiation treatment followed by pulverized basal diet containing 0% (Group 2), 2% (Group 3) or 4% (Group 4) kojic acid (KA) were examined at Weeks 1, 2, 4, 8 and 12. As an untreated control group (Group 1), rats were given basal diet for 13 weeks and examined in the same manner. Serum T3/T4 levels in the DHPN+2% KA and DHPN+4% KA groups were significantly reduced as compared with the DHPN-alone group at each time point. Serum TSH levels in both DHPN+KA groups were significantly increased at each time point in a treatment period-dependent manner from Weeks 1 to 12, and the extent of elevation was more remarkable in the DHPN+4% KA group. At Week 2, there were no statistically significant intergroup differences in liver T4-UDP-GT activities on a milligram microsomal protein basis. Histopathologically, no thyroid proliferative lesions were observed in the untreated control group or the DHPN-alone group. However, diffuse follicular cell hypertrophy and decreased colloid in the thyroid were apparent in all rats of the DHPN+KA groups at each time point. In addition, local follicular cell hyperplasias and adenomas of the thyroid were observed at high incidence in the DHPN+2% KA group from Week 4 and in the DHPN+4% KA group from Week 8. Multiplicities of focal follicular cell hyperplasias and adenomas of the thyroid in the DHPN+2% KA group were significantly greater than those in the DHPN+4% KA group at Week 8. In the pituitary, an increase in the number of TSH producing cells with expanded cytoplasm was apparent from Weeks 4 to 12 in both DHPN+KA groups. These results strongly suggest that thyroid proliferative lesions were induced by KA administration due to continuous serum TSH stimulation through the negative feedback mechanism of the pituitary-thyroid axis, resulting from depression of serum T3 and T4.