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β-Adrenergic Antagonist Inhibition of Hepatic 3,5,3'-Triiodothyronine Production^*

Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine Chapel Hill, North Carolina 27514

Address requests for reprints to: Dr. Robert D. Utiger, Department of Medicine, Division of Endocrinology, University of North Carolina, Chapel Hill, North Carolina 27514.

Abstract

β-Adrenergic antagonists provide moderate symptomatic relief for most hyperthyroid patients, although these agents have no direct antithyroid effects. Propranolol administration results in modest declines in serum T₃ concentrations in both hyperthyroid and normal subjects and also inhibits T₄ to T₃ conversion in various tissue preparations in vitro. Other β-adrenergic antagonists have not been shown to consistently alter serum T₃ concentrations in vivo or T₃ production in vitro. To evaluate the ability of β-adrenergic antagonists to inhibit T₄-5'-deiodination, we measured T₃ production from T₄ in rat liver homogenates (10,000 x g supernatant) using 1 pM T₄ in the presence of varying concentrations of the β-adrenergic antagonists available in the United States. Each drug inhibited T₃ production, and the dose-dependent responses were linear and parallel when plotted as percent inhibition vs. log dose concentration. The calculated drug concentrations required to produce 50% inhibition were: propranolol, 1.7 mM; pindolol, 6.7 mM; timolol, 11.5 mM; atenolol, 23.2 mM; metoprolol, 30.5 mM, and nadolol, 106.1 mM. The IC₅₀ values were similar in the presence of 4 mM dithiothreitol. In separate studies, the ability of D- and L-propranolol to inhibit T₃ production was compared with that of D,L-propranolol, the common form. Both _d- and _l-propranolol were as effective as the racemic mixture. The pro-pranolol metabolites 4-hydroxypropranolol, 4-methylproprano-lol, propranolol glycol, and N-desisopropyl propranolol were also effective inhibitors. Thus, β-adrenergic antagonists inhibit T₃ production in vitro. This inhibition is not related to β-adrenergic antagonism per se, but is correlated with the lipid solubility of the drugs, which may explain the effects of propranolol on serum T₃ in vivo. (Endocrinology 115: 858–861, 1984)

Footnotes

^* Presented in part at the 59th Annual Meeting of the American Thyroid Association, New Orleans, LA, 1983. This work was supported by USPHS Grants AM-26112 and AM-7129.

Received February 14, 1984.