Promoting effects of xylazine on development of thyroid tumors in rats initiated with N-bis(2-hydroxypropyl)nitrosamine and the mechanism of action

To cast light on whether xylazine hydrochloride (XZ), a veterinary medicine commonly used as a sedative agent for food-producing animals, has any prom oting potential for thyroid carcinogenesis, the following studies were perf ormed, In Experiment I, male F344 rats received a diet containing 1000 or 0 p.p.m, XZ for 52 weeks with or without initiation with 2400 mg/kg N-bis(2- hydroxypropyl)nitrosamine (DHPN), Focal follicular cell hyperplasias, adeno mas and/or carcinomas were induced in the DHPN alone, XZ alone and DHPN + X Z groups, and the incidences and multiplicities of these lesions in the DHP N + XZ group were significantly increased as compared with the DHPN alone c ase. In Experiment II, male F344 rats received a diet containing 1000 or 0 p,p,m, XZ and were examined for serum levels of triiodothyronine (T-3), thy roxine (T-4) and thyroid-stimulating hormone (TSH) at weeks 1, 2 and 4, In the XZ group, significant increase in thyroid weight and decrease in serum T-4 levels were observed at all time points. Serum T-3 and TSH levels were significantly decreased and increased, respectively, at week 1, but returne d to within the control range thereafter, In Experiment III, male F344 rats received a diet containing 1000 or 0 p,p,m, XZ, they were examined for thy roid iodine uptake and organification of XZ after 1 and 2 weeks. The thyroi dal iodine uptake per milligram of thyroid and the amount of iodine bound t o 1 mg protein showed a tendency for decrease at week 1 and significant dec rease at week 2, These results indicate that XZ has tumor-promoting effects on thyroid follicular cells, and suggest an involvement of alterations in thyroid-related hormone levels due to inhibition of thyroid iodine uptake a nd organification, resulting, provably, in serum TSH stimulation depending on continuous reduction of serum T-4 level through the feedback system in t he pituitary-thyroid axis.