Molecular orbital studies of the action of thyroid hormone analogs: Effects on oxygen consumption of mitochondria and horseradish peroxidase-catalyzed NADH oxidation

The electronic structure of thyroxine and related compounds were calculated by semiempirical molecular orbital methods. When the quantum chemical indices obtained were compared with the structure-activity relationship obtained so far byin vivo andin vitro assays, it was found that HOMO (highest occupied molecular orbital) energy levels of thyroxine and its analogs are well correlated with the increase in oxygen consumption of rat kidney mitochondria determined byin vitro assay. This finding permits the hypothesis that these compounds may play a role in activating the electron transport system of mitochondria by mediating the oxidation-reduction of cytochromes. Furthermore, HOMO energy levels of thyroxine and phenol derivatives were found to correlate well with the stimulation of horseradish peroxidase-catalyzed oxidation of NADH. This suggests that the step of electron removal from these compounds by the enzyme system may be a rate-limiting step, confirming the view that phenoxy-radicals meditate the whole reaction.