Metabolic effects of thyroid hormones in vitro. II. Influence of thyroxine and triiodothyronine on oxidative phosphorylation.

Because of the profound effect of thyroxine on the metabolic rates of animals, several groups of investigators have sought a relationship between this hormone and oxidative phosphorylation (14). The work in this laboratory was designed to test the hypothesis that the thyroid hormone may exert its salutary effects by uncoupling an oxidative phosphorylation just prior to a rate-limiting step in the electron transport sequence (5). The toxic manifestations of the hormone would result from the same action carried beyond the point of benefit. In support of the hypothesis, enzyme preparations from livers of hyperthyroid rats were found to be less efficient in coupling phosphorylation with oxidation than were preparations from normal rats (1). Under specified conditions, thyroxine added to normal tissue preparations in vitro was found to depress P:O ratios, although it also depressed respiration (1). Martius and Hess (4) have reported that thyroxine applied in vivo or in vitro inhibits uptake of radioactive orthophosphate by rat liver mitochondria. However, they reported no data for oxygen consumption. Since thyroxine inhibits respiration in some systems (1,2), it is essential to measure both respiration and phosphorylation in experiments of this type. Triiodothyronine has recently been identified by Gross and Pitt-Rivers (6) as a plasma-borne, iodine-containing compound which may be produced from thyroxine even in thyroidectomixed animals (7). Triiodothyronine has been synthesized (6, S), and Gross and Pitt-Rivers (9) have demonstrated that it is 3 to 4 times as active as thyroxine in preventing thyroid enlargement in rats fed thiouracil. Its influence on myxedematous patients is manifested by an increased basal metabolic rate, decreased body weight, and decreased cholesterol of the blood (10). In this paper data are presented which demonstrate that thyroxine and triiodothyronine added in vitro depress oxidative phosphorylation by rat