Effect of Thyroid Hormone on the Substrate Interaction with P-450 in the Oxidation of Drugs by Liver Microsomes

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Abstract
The administration of thyroxine to male rats decreased the content of P-450 and the magnitude of spectral change of P-450 induced by various drugs in hepatic microsomes. The magnitudes of spectral changes per P-450 induced by hexobarbital and aminopyrine were decreased, whereas those induced by aniline and zoxazolamine were not significantly affected. In contrast to the results observed with male rats, the magnitudes of the spectral changes induced by hexobarbital and aminopyrine were not significantly decreased in microsomes from thyroxine-treated female rats. These results suggest that the binding capacity of P-450 with hexobarbital and aminopyrine was decreased by thyroxine probably through an impairment of androgen action to increase the binding capacity of P-450. The decrease in the binding capacity of P-450 with hexobarbital and aminopyrine is assumed to be a responsible factor for the decrease in the activities of hexobarbital hydroxylation and aminopyrine N-demethylation. Since the ratios of the hydroxylating activities of the drugs to the magnitudes of spectral changes were increased in microsomes from thyroxine-treated rats, the increase in the rate of the reduction of P-450-drug complex has been suggested. Thyroidectomy did not affect the content of P-450, but decreased the binding capacity of P-450 with hexobarbital and aminopyrine in the males. Since the ratios of the hydroxylating activities of the drugs to the magnitudes of spectral changes were decreased in microsomes from thyroidectomized rats, the decrease in the rate of the reduction of P-450-drug complex has been suggested. The Km (Michaelis constant) values and K3 (spectral dissociation constant) values for hexobarbital were increased in microsomes from thyroxine-treated male rats, whereas the Km and K3 values for aniline were not affected. Since the Km and K3 values for hexobarbital are clearly dependent on androgen, these results again suggest the impairment of androgen action in thyroxine-treated male rats.

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