Effect of adrenalectomy and cortisone administration on components of the liver microsomal mixed function oxygenase system of male rats which catalyzes ethylmorphine metabolism

Abstract

The effects of adrenalectomy and cortisone administration on components of the mixed function oxygenase system of liver microsomes from adult male rats were studied. The N-demethylation of ethylmorphine (EM) as measured by formaldehyde production was used as an index of the overall activity of this system. EM demethylase activity in liver microsomes from adrenalectomized rats was 56 per cent of the value obtained with sham-operated controls, while cytochrome P-450 content fell by only 19 per cent. NADPH cytochrome c reductase and cytochrome P-450 reductase activities were decreased 68 and 69 per cent, respectively, in liver microsomes from adrenalectomized animals, while the apparent affinity constant ( K sp ) of EM for cytochrome P-450 spectral change was not altered. The decrease in maximal spectral change caused by adrenalectomy corresponded to the decrease in cytochrome P-450 content. Cortisone acetate administration (5 mg/kg/day for 8 days) to adrenalectomized rats prevented the decrease in EM demethylase activity. Accordingly, the steroid treatment increased the NADPH cytochrome c reductase and cytochrome P-450 reductase activities to 113 and 140 per cent, respectively, of the values obtained with the sham-operated controls, without significantly altering the cytochrome P-450 content or the kinetic constants for the spectral changes. These data suggest that the well known decrease in drug-metabolizing activity seen in liver microsomes of adrenalectomized animals is not related to changes in cytochrome P-450 content or to a decrease in the ability of cytochrome P-450 to bind drug substrates. However, there appears to be a relationship between the reductase activities and the adrenal function, because the changes in activities in NADPH cytochrome c reductase and cytochrome P-450 reductase in liver microsomes from adrenalectomized and cortisone-treated adrenalectomized rats paralleled the changes in EM demethylase activity.