Suppression by antithyroid drugs of experimental hepatic necrosis after ethanol treatment. Effect on thyroid gland or on peripheral deiodination?
Britton, R.S.; Koves, G.; Orrego, H.; Kalant, H.; Phillips, M.J.; Khanna, J.M.; Israel, Y.
Toxicology and Applied Pharmacology 51(1): 145-155
1979
ISSN/ISBN: 0041-008X PMID: 93320 Document Number: 143184
The antithyroid drug 6-n-propyl-2-thiouracil (6-n-PTU) suppressed the production of liver necrosis in ethanol-treated rats subjected to hypoxia. 6-n-PTU reduced the thyroidal state by blocking thyroid hormone synthesis and by inhibiting the peripheral thyroxine (T4) deiodination to triiodothyronine. The effects of greater importance in affording protection against hepatic necrosis in these animals were determined. 2-S-methyl-5-n-propyl-2-thiouracil (S-methyl-5-n-PTU), a new compound, was as effective as 6-n-PTU in decreasing T4 deiodination but had less than 1% of the potency of 6-n-PTU in inhibiting thyroidal I- incorporation. Methimazole blocked thyroid hormone synthesis but did not affect T4 deiodination. These drugs were administered to adult male rats in liquid diet for 10 days at a dose of 230 .mu.mol/kg per 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 h. 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. The protective action of 6-n-PTU against hypoxia-induced liver damage in ethanol-treated animals may be more closely associated with its ability to decrease the synthesis of thyroid hormones than with its ability to inhibit T4 deiodination.