Effects of thyroxine on the expression of alcohol dehydrogenase in rat liver and kidney

Abstract

We studied the effect of thyroxine on alcohol dehydrogenase activity, immunoreactive protein levels and messenger RNA levels in the livers of thyroidectomized and sham-operated male rats. Effects on kidney alcohol dehydrogenase activity were also examined. Sham-operated rats injected with 100 micrograms thyroxine/kg/day, which induced hyperthyroidism, showed a 30% decrease in liver and a 40% decrease in kidney alcohol dehydrogenase activity compared with sham-operated rats injected with vehicle. Hypothyroid rats exhibited a 1.5-fold increase in alcohol dehydrogenase activity in liver and kidney compared with thyroidectomized rats injected with a replacement dose of 20 micrograms thyroxine/kg/day. We saw a twofold and a 2.5-fold higher level of alcohol dehydrogenase activity in liver and kidney, respectively, of hypothyroid rats compared with hyperthyroid rats. These effects were not accounted for by nutritional differences; daily food intake did not differ between groups. Immunoreactive protein levels as seen on Western blots varied in the same direction as enzyme activity. Northern-blot analysis showed higher levels of liver alcohol dehydrogenase messenger RNA in hypothyroid rats compared with euthyroid rats. These studies show that liver alcohol dehydrogenase activity and protein levels are modulated by thyroxine at pathophysiologically relevant levels and that this effect is not due to changes in food intake; kidney alcohol dehydrogenase activity is regulated in parallel. The change in alcohol dehydrogenase activity appears to be controlled in part by pretranslational mechanisms in hypothyroid animals and by posttranslational mechanisms in hyperthyroid animals.

Sexual dimorphic expression of ADH in rat liver: importance of the hypothalamic-pituitary-liver axis

“…The molecular mechanism(s) accounting for thyroid repression of ADH either alone or with GH is not clear. A putative thyroid response element has not been demonstrated in the rat promoter (14), but Harding and Duester (22a) have demonstrated that thyroid may compete at retinoic acid receptor elements in the human promoter. However, in the intact animal, thyroid hormone was also shown to regulate circulating levels of GH that might, in turn, regulate ADH.…”

“…Administration of corticosterone-21-acetate either alone or with GH to Hx male rats did not alter either ADHspecific activity or mRNA levels (data not shown). On the other hand, thyroid hormone, which was previously implicated in the downregulation of ADH-specific activity and mRNA levels in intact rats (14,38), was demonstrated to be an important component of ADH sexual dimorphic expression. Because previous studies had not considered the indirect effect of thyroid hormone on GH secretion (7), we examined the effect of T 4 both alone and in combination with GH on hepatic ADH-specific activity and mRNA in Hx male and female rats.…”

“…Therefore, it is unclear whether exogenous sex steroid hormones alter expression of ADH directly or indirectly through changes in GH secretion. Additionally, thyroidectomy increased hepatic ADH in both sexes, which may be a direct effect or possibly secondary to modulation of serum GH levels (14). In contrast, adrenalectomy had no effect in male rats (39).…”

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology

“…In vitro promoter studies suggest that the genes are regulated (retinoic acid and glucocorticoids activating transcription and thyroid hormone antagonizing the effect of retinoic acid; Harding & Duester, 1992), but smaller effects are seen in vivo. This disparity may be the result of effects of the hormones on protein synthesis and turnover as well as on transcription (Qulali & Crabb, 1992;Dipple et al 1993). Growth hormone increased ADH activity in intact animals and cultured hepatocytes (Mezey & Potter, 1979;Mezey et al 1986b;Potter et al 1989Potter et al , 1993, while androgens (Mezey et al 1986a) and thyroid hormones (Mezey & Potter, 1981;Dipple et al 1993) decreased it.…”

“…This disparity may be the result of effects of the hormones on protein synthesis and turnover as well as on transcription (Qulali & Crabb, 1992;Dipple et al 1993). Growth hormone increased ADH activity in intact animals and cultured hepatocytes (Mezey & Potter, 1979;Mezey et al 1986b;Potter et al 1989Potter et al , 1993, while androgens (Mezey et al 1986a) and thyroid hormones (Mezey & Potter, 1981;Dipple et al 1993) decreased it. Liver ADH activity is also decreased substantially by fasting (Bosron et al 1984) and protein restriction (Lumeng et al 1979).…”