Kynurenine metabolism in hyperthyroidism. A biochemical basis for the low NAD(P) level in hyperthyroid rat liver.

Subcutaneous administration of L-thyroxine (75 pg/lOO g of body weight per day) to rats for 10 to 14 days caused a decrease in the activity of kynurenine 3-hydroxylase to about 50% of the control value. Enzymic properties of kynurenine 3-hydroxylase of mitochondrial outer membrane preparations isolated from normal and L-thyroxine-treated rats were almost identical, suggesting that L-thyroxine acted by controlling the amount rather than the structure of. kynurenine 3hydroxylase. Analyses of the time course of changes in enzyme activities following the institution and withdrawal of L-thyroxine indicated that the decreased level of kynurenine 3-hydroxylase was caused by a decreased synthesis of the enzyme, rather than an increased degradation. In contrast, the activity of kynurenine aminotransferase localized in the mitochondrial inner membrane was increased about 16 times by L-thyroxine administration. This L-thyroxine-induced rise in kynurenine aminotransferase activity was completely inhibited by ethionine or cycloheximide, suggesting that L-thyroxine induced the de novo synthesis of kynurenine aminotransferase. Kynurenine hydrolase, an extramitochondrial enzyme, was not affected however by the hormone. These enzyme patterns observed in hyperthyroid rats were consistent with the urinary levels of kynurenine and its metabolites. These results are considered in terms of the NAD(P) synthesis from tryptophan in hyperthyroidism.