Rapid stimulation of hepatic microsomal heme oxygenase in selenium-deficient rats. An effect of phenobarbital.

M.A Correia,R.F Burk

doi:10.1016/s0021-9258(17)34600-8

Abstract

Hepatic microsomal heme oxygenase, the rate-limiting enzyme in heme degradation, is rapidly and markedly stimulated in selenium-deficient rats but not in controls, after a single injection of phenobarbital sodium. This stimulation occurred as early as 2 h and reached an 8- to 10-fold maximum 6 h following the drug. These observations suggest that phenobarbital rapidly and markedly enhances the degradation of hepatic heme in selenium deficiency. The cause for this rapid phenobarbital-mediated stimulation of heme degradation was investigated. It could not be ascribed to either accelerated turnover of cytochrome P-450, or enhanced lipid peroxidation possibly resulting from the concomitant lack of glutathione peroxidase in selenium deficiency. For these reasons, the metabolism of hepatic heme in the selenium-deficient rat liver was further examined during the 6-h period following phenobarbital. These studies indicated that whereas heme was synthesized much faster and to a greater extent in the selenium-deficient rat liver than in the control, its utilization in the formation of hemoproteins such as cytochrome P-450 and tryptophan pyrrolase was apparently impaired in selenium deficiency. Such defective utilization of heme in the 6-h period following phenobarbital could effectively result in a relative excess of unutilized "free" heme; hence the consequent stimulation of microsomal heme oxygenase for its disposal.

Highlights

From the Departments of Medicine and Pharmacology and The Liver Center, University of California, San Francisco, California 94143 and the Liver-GI Unit, Department of Internal Medicine and Department of Biochemistry, University of
We recently investigated the mechanism responsible for the impairment of phenobarbital-mediated induction of liver cytochrome P-450 which occurs in selenium-deficient rats [1,2]
Oxygenase Activity and Cytochrome P-450 Turnover in Selenium Deficiency-Following a single injection of phenobarbital, microsomal heme oxygenase activity in the seleniumdeficient rat liver increased 2- to 3-fold at 2 h and reached a maximum (8- to lo-fold) at 6 h before declining (Fig. 1)

Summary

Introduction

Further experiments indicated that in selenium deficiency a single injection of phenobarbital produces a rapid stimulation of microsomal heme oxygenase activity in the rat liver, detectable as early as 2 h after administration of the drug (Fig. 1). Phenobarbital provokes a rapid and marked increase in microsomal heme oxygenase activity in the selenium-deficient rat liver. Phenobarbital fails to stimulate hepatic microsomal heme oxygenase activity in control (selenium-adequate) rats, examined after either a single injection (Fig. 1) or repeated administration of the drug [1, 2].

Results

Conclusion