Effects of a synthetic retinoid, etretinate (RO 10-9359), on the peripheral metabolism of thyroid hormones in rats

Abstract

Male Wistar rats were administered a synthetic vitamin A compound, etretinate, at various doses, including levels exceeding recommended therapeutic doses. At 2 mg/kg body weight/day given intragastrically, no effects were detected with respect to serum retinol or thyroid hormones after 15 days of treatment. At 5 mg/kg/day only a slight decrease in serum triiodothyronine was detected. In contrast, the dose of 20 mg/kg/day for 15 days resulted in relatively severe effects: body weight was decreased by 23% in comparison with the controls, serum retinol was decreased by 62% (while liver stores of vitamin A were unaffected), and serum thyroxine and triiodothronine levels were, respectively, 24 and 29% lower than in the controls. A kinetic study demonstrated that the biological half-life of serum thyroxine decreased by 62% and that of serum triiodothyronine by 24%, suggesting increased peripheral metabolism of the thyroid hormones. The two main metabolic pathways (i.e. hepatic 5′-monodeiodination and glucuronide conjugation) were not significantly affected by etretinate treatment and do not account for the apparent metabolic loss of the thyroid hormones. This experiment demonstrates that etretinate doses beyond the therapeutic range are required to imbalance thyroid hormone homoeostasis. Possible mechanisms relating to increased hormonal clearance in rats treated with high doses of etretinate are discussed.