Effect of manganese on the hepatic microsomal mixed function oxidase enzyme system in the rat.

Experiments were conducted to examine the effect of manganese on the hepatic mixed function oxidase system in the rat. Acute treatment with manganese chloride (1-10 mg Mn/kg, ip) produced a significant prolongation of hexobarbital hypnosis in male rats on Days 2 and 3 following metal administration. The threshold dose of manganese to produce this alteration in response was 5 mg Mn/kg and the altered response returned to control values by Day 5. The prolonged hexobarbital hypnosis resulted from Mn inhibition of the hepatic microsomal mixed function oxidase system, the activity of which was assessed using aniline (23%), ethylmorphine (26%), and hexobarbital (27%) as substrates. Manganese treatment also produced significantly reduced levels of cytochrome P-450 (23%) and b5 (21%), but the substrate-induced spectral binding of all three substrates was not altered significantly by Mn when expressed as delta A per nanomole of cytochrome P-450. The activity of NADPH cytochrome c reductase was also significantly decreased (25%) by Mn treatment. Following the in vitro addition of Mn in concentrations ranging from 1 X 10(-6) to 1 X 10(-3) M Mn to microsomes derived from naive rats, there was no decrease in the metabolism of aniline or hexobarbital or cytochrome P-450 levels. Significant inhibition in ethylmorphine metabolism was observed with Mn concentrations of 1 X 10(-4) M and greater. These experiments indicate that acute Mn treatment can alter drug response as the result of decreased hepatic biotransformation which occurs by an indirect mechanism.

Effect of manganese on hepatic drug metabolism in male and female rats.

Experiments were conducted to examine the effect of manganese on drug response and metabolism in male and female rats. Three days after administration of manganese chloride (5 mg Mn/kg, ip), the duration of hexobarbital hypnosis was prolonged in male but not in female rats. Hepatic microsomal metabolism of aniline, ethylmorphine, and hexobarbital was significantly inhibited in male rats. Metabolism of aniline and ethylmorphine was also inhibited in female rats but to a lesser extent than in males. Hexobarbital metabolism was not inhibited in female rats. Cytochrome P-450 content was depressed only in male rats, while cytochrome b5 levels were decreased in both sexes. These results indicate that sex-related differences exist in the ability of manganese to alter drug response and metabolism.

Interaction between manganese and phenobarbital on hexobarbital hypnosis in the male rat.

Pretreatment of male rats with phenobarbital markedly decreases while treatment with manganese prolongs the duration of hexobarbital hypnosis in male rats. When both agents were administered simultaneously, the manganese-induced prolongation of hexobarbital was prevented.

Effect of acute and repeated selenium treatment on hepatic monooxygenase enzyme activity in male rats.

The effect of sodium selenite administered acutely or repeatedly on the biochemical components of the hepatic microsomal monooxygenase enzyme system was examined in male rats. 72 h following acute administration of selenium (2.4 mg Se/kg, i.p.), there was a significant decrease in ethylmorphine-N-demethylase activity and cytochrome P-450 levels but no change in aniline hydroxylase or NADPH cytochrome c reductase activity. Following repeated administration of selenite in the drinking water (1, 2, or 4 ppm Se) for 30 days, there was no alteration in any of the parameters measured. Following the in vitro additions of selenite to microsomes obtained from untreated rats, ethylmorphine-N-demethylase and aniline hydroxylase activities were inhibited at selenium concentrations of 10(-4) M or greater, but the inhibition achieved was less than 50%. No alterations in cytochrome P-450 levels were observed. These results indicate that selenium is a rather weak, indirect, and substrate-specific inhibitor of the hepatic monooxygenase enzyme system.

Circadian rhythms in the biological response and disposition of ethanol in the mouse.

Circadian rhythms in the response to ethanol were investigated in male, Swiss-Webster mice. Significant circadian variations were observed in increased and decreased spontaneous locomotor activity induced by ethanol (2 or 4 mg/g i.p., respectively) and in the hypothermic response to ethanol with the greatest effect generally occurring during the dark phase of the 12 hr:12 hr. light-dark cycle when the normal activity of the animals was highest. Ethanol was also more lethal during the dark phases as compared to the light phase. Disposition studies showed that the in vivo rate of disappearance of ethanol from the blood and the in vitro metabolism of ethanol by hepatic alcohol dehydrogenase were invariant throughout the 24-hr period. Additional studies demonstrated that the duration of ethanol-induced hypnosis was longer and the concentration of ethanol in blood and brain tissue, at awakening, was lower during the dark phase as compared to the light phase. These data suggest that circadian rhythms observed in the pharmacological and toxicological effects of ethanol in mice do not result from daily fluctuations in drug disposition but are more likely subserved by temporal changes in the sensitivity of the central nervous system to ethanol.

Lack of effect of cadmium on the biological response to and metabolism of ethanol in vivo.

Following the administration of cadmium (2 mg/kg) neither the duration of hypnosis nor the in vivo rate of tissue decline of ethanol was altered. These results differ from the cadmium-induced alterations in biological response and metabolism of other centrally acting drugs.