SUPPRESSION BY ANTI-THYROID DRUGS OF EXPERIMENTAL HEPATIC-NECROSIS AFTER ETHANOL TREATMENT - EFFECT ON THYROID-GLAND OR ON PERIPHERAL DEIODINATION

The antithyroid drug 6-n-propyl-2-thiouracil (6-n-PTU) suppresses the production of liver necrosis in ethanol-treated rats subjected to hypoxia. 6-n-PTU reduces the thyroidal state by blocking thyroid hormone synthesis and by inhibiting the peripheral deiodination of thyroxine (T4) to triiodothyronine. We determined which of these effects was of greater importance in affording protection against hepatic necrosis in these animals. 2-S-Methyl-5-n-propyl-2-thiouracil (S-methyl-5-n-PTU), a new compound synthesized by us, was shown to be as effective as 6-n-PTU in decreasing the deiodination of T4 but had less than 1% of the potency of 6-n-PTU in inhibiting thyroidal iodide incorporation. Methimazole blocks thyroid hormone synthesis but does not affect T4 deiodination. These drugs were administered to adult male rats in liquid diet for 10 days at a dose of 230 μmol/kg/day. On Day 10, the rats were given either a liquid diet containing ethanol (35% of calories) or isocaloric sucrose, and on Day 11 all animals were exposed to 5% O2 for 6 hr. One day of ethanol ingestion markedly increased the degree of hepatic necrosis after hypoxia: This damage was suppressed by 6-n-PTU and methimazole, but not by S-methyl-5-n-PTU. Therefore, the protective action of 6-n-PTU against hypoxia-induced liver damage in ethanol-treated animals appears to be more closely associated with its ability to decrease the synthesis of thyroid hormones than with its ability to inhibit T4 deiodination. © 1979.