On the Mechanism of Impaired in Vitro Generation of 3,5,3′-Triiodothyronine from Thyroxine in the Livers of Hypothyroid Rats*

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Abstract
It has been demonstrated previously that in rat liver, the generation of T3 from T4 (T3) neogenesis) is mediated by an enzyme present in the crude microsomal fraction and that the activity of the enzyme is enhanced by cofactors present in the cytosol. The present studies were undertaken to evaluate the respective roles of microsomal and cytosolic factors in producing the impaired hepatic T3 neogenesis previously shown to occur in hypothyroid rats. To this end, T3 neogenesis was assessed in mixtures of microsomes and buffer or microsomes and cytosols from intact and thyroidectomized rats in the presence and absence of added cofactors. Regardless of whether studies were conducted with buffer, normal cytosol, or cytosol from hypothyroid animals, microsomes from normal animals consistently generated more T3 from T3 than did microsomes from hypothyroid animals. Moreover, although glutathione (GSH) in buffer greatly stimulated T.i neogenesis in control microsomes, it had little such effect in microsomes from hypothyroid animals. A secondary and less severe abnormality appeared to be present in the hepatic cytosol from hypothyroid rats, since T3 neogenesis was consistently greater in the presence of control cytosol than when cytosol from hypothyroid animals was used. As judged from studies with control microsomes, the defect in supporting activity of cytosol from hypothyroid animals was abolished by the addition of NADPH or GSH. The findings indicate that the major factor responsible for defective T3 neogenesis in the liver of the hypothyroid rat is a decrease in the activity of the 5′-monodeiodinase for T4 present in the crude hepatic microsomal preparation. It is not clear, however, whether the decrease reflects a change in the concentration of enzyme or a change in its properties leading to decreased responsiveness to stimulatory cofactors. A secondary abnormality in hepatic T3 neogenesis is evidently a reduction in the supporting activity of the cytosol, possibly reflecting a decrease in the concentrations of NADPH or GSH, or both.

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