EFFECT OF MANGANESE ON DRUG ACTION AND THE PROTECTIVE ROLE OF ZINC, SELENIUM, AND SUBTHRESHOLD MANGANESE

MICHAEL JOSEPH DEIMLING, Purdue University

Abstract

This study was undertaken to examine the effect of manganese on drug response and hepatic drug metabolism in male and female rats and male mice. Additionally, the effects of zinc, selenium, and subthreshold manganese on manganese-induced alterations of drug action and metabolism were investigated. Dose-response studies in male rats demonstrated that a threshold manganese dose of 3 to 5 mg Mn('++)/kg, administered intraperitoneally as the chloride salt, resulted in significant prolongation of both pentobarbital- and hexobarbital-induced hypnosis three days following metal administration. Additionally, time-course studies in the male rat indicated that a manganese dose of 5 mg Mn('++)/kg (i.p.) produced significant prolongation of hexobarbital hypnosis two and three, but not one, days following manganese administration. Examination of in vitro hepatic drug metabolism three days following manganese (5 mg Mn('++)/kg, i.p.) administration to male rats revealed significant decreases in the rates of aniline, ethylmorphine, and hexobarbital metabolism by the microsomal fraction. Concurrently, the levels of hepatic cytochromes P-450 and b(,5) were also decreased. The hepatic microsomal spectral binding of aniline, ethylmorphine, and hexobarbital was generally unchanged by manganese treatment. The in vitro addition of manganese (10('-6) to 10('-3) M) to hepatic microsomes from untreated male rats produced no significant effect on either hexobarbital or aniline metabolism, although, ethylmorphine metabolism was inhibited at the two highest concentrations employed. Furthermore, in vitro addition of identical concentrations of manganese to microsomal suspensions from untreated male rats did not significantly alter the level of cytochrome P-450 Additional investigations revealed that female rats and male mice were less sensitive to the hepatic effects of manganese as compared to male rats. Manganese doses (5 mg Mn('++)/kg, i.p.) shown to produce enhanced drug response in the male rat, had no effect in female rats or male mice. Further studies in female rats demonstrated that manganese treatment decreased the rates of in vitro hepatic microsomal metabolism of aniline, ethylmorphine, and hexobarbital without producing a concurrent decrease in the level of hepatic cytochrome P-450. Spectral binding of all three substrates was unchanged in treated as compared to untreated female rats. The duration of ethanol-induced hypnosis was unaffected by the administration of manganese doses (5 mg Mn('++)/kg, i.p.) shown to prolong the duration of both pentobarbital and hexobarbital hypnosis in the male rat. Phenobarbital treatment for three days prior to, and concurrent with, manganese treatment protected against manganese-induced prolongation of hexobarbital-induced hypnosis in the male rat. Treatment with zinc acetate (6 mg Zn('++)/kg, i.p.), sodium selenite (1.6 mg Se('++)/kg, i.p.), or subthreshold manganese (1 mg Mn('++)/kg, i.p.) three days prior to challenge with a threshold dose of manganese (5 mg Mn('++)/kg, i.p.) also protected against manganese-induced alterations of drug response and metabolism. Additional investigations indicated that these effects resulted from protection against manganese-induced decreases of hepatic cytochrome P-450. Spectral binding was not consistently altered. The results of these studies indicate that manganese treatment decreases hepatic drug metabolism in the male rat, most likely by indirectly decreasing the level of hepatic cytochrome P-450, resulting in enhanced drug response. Moreover, this effect shows both sex and species dependency. The administration of zinc, selenium, and subthreshold manganese protects against manganese-induced decreases of hepatic cytochrome P-450 thus protecting against manganese-induced alterations of drug response and metabolism.

Degree

Ph.D.

Subject Area

Pharmacology

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