Manganese and zinc blockade of enzyme induction: Studies with microsomal heme oxygenase

Abstract

Heme oxygenase (decyclizing) [heme,hydrogen-donor:oxygen oxidoreductase (a-methene-oxidizing, hydroxylating), EC 1.14.99.3] is greatly induced in the kidney by the administration of nickel or tin. Manganese, when administered simultaneously with nickel or tin in an equimolar amount, substantially inhibited the induction of heme oxygenase. The extent of inhibition was 80% and 98%, respectively. In rats pretreated up to 8 hr with manganese, the level of induction of heme oxygenase by nickel or tin was markedly reduced in a time-dependent fashion. Manganese treatment after the inducing metat was relatively ineffective in preventing the induction of heme oxygenase. Manganese in vitro did not inhibit heme oxygenase in the microsomes isolated from either control or tin-induced rats and in vivo did not increase the rate of catabolism of the induced enzyme. Magnesium was unable to block nickel or tin induction of heme oxygenase. Zinc in equimolar amounts could also substantially reduce the extent o induction of renal heme oxygenase when administered simultaneously with nickel or tin. In addition, simultaneous zinc administration blocked to a considerable extent the induction of hepatic heme oxygenase by nickel, cobalt, or cadmium. These findings indicate the existence of metal-metal interactions that can greatly influence the regulatory mechanism for the induced synthesis of heme oxygenase, the rate-limiting enzyme in heme degradation. Earlier studies from this laboratory showed that a number of transition elements and heavy metals are potent inducers of heme oxygenase (decyclizing) [heme,hydrogen-donor:oxygen oxidoreductase (a-methene-oxidizing, hydroxylating), EC 1.14.99.3] (1-3), the microsomal enzyme that catalyzes the rate-limiting step in the catabolism of heme to bile pigment (4, 5). Concomitant with the metal-induced increase in heme oxygenase there is generally a decrease in microsomal heme and cytochrome P-450 levels and an impairment in the activity of the mixed function oxidase system (2, 3, 6, 7). If these detrimental effects of exogenous metals on heme metabolism could be readily blocked, cellular mechanisms for carrying out cytochrome P-450-dependent detoxification of drugs and related chemicals would be expected to be maintained at normal levels.We report in this communication that the induction of microsomal heme oxygenase by certain trace elements can be prevented by the administration of other metals. Specifically, manganese and zinc are shown to be potent inhibitors of tinand nickel-mediated induction of heme oxygenase in the kidney, whereas zinc can substantially reduce the extent of induction of hepatic heme oxygenase by cobalt, cadmium, and nickel. This inhibition of metal induction of heme oxygenase is associated with a diminution of the decline usually observed in microsomal heme and cytochrome P-450 content as well as in the activity of the mixed function oxidase system. The se-The publication costs of this article were defrayed in part by page charge payment. This article must therefor...

Control of heme and cytochrome P-450 metabolism by inorganic metals, organometals and synthetic metalloporphyrins.

“…For example, manganese when administered simultaneously with tin prevents the increase in heme oxygenase induced by the latter metal (Fig. 2); zinc also has the same blocking effect (11). Manganese and zinc administration also prevents the decline in cytochrome P-450 content and the changes in ALA-synthase activity associated with tin administration.…”

“…Each inablity of Sn-protoporphyrin to induce heme oxygenf at least three animals killed at the ase activity in kidney (Fig. 6) whereas inorganic tin is a powerful inducer of the enzyme in this organ (5,11). Whether the potent inhibitory effect of Sn-protoa similar suppressive effect porphyrin on heme oxygenase activity obscures an )ut other metalloporphyrins underlying ability of the metalloporphyrin to also inporphyrin and Zn-protoporduce de novo synthesis of the enzyme protein remains to ly large amounts, show this be determined by appropriate immunological means.…”

Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation.

“…Chemical blockade of the postnatal induction of heme oxygenase activity [heme,hydrogen-donor:oxygen oxidoreductase (amethene-oxidizing, hydroxylating), EC 1.14.99.3] and suppression of the hyperbilirubinemia that results from fetal erythrocyte lysis and exaggerated heme oxidation during this period has not been demonstrated in the whole animal. Total blockade of heme oxygenase induction by certain transition and related elements can, however, be achieved by concurrent administration of other metal ions (1,2). Moreover, certain synthetic metalloporphyrins, as we earlier demonstrated (3), can act as competitive substrates for heme in the.…”

The Comparative Abilities of Inorganic Cobalt and Cobalt-Protoporphyrin to Affect Copper Metabolism and Elevate Plasma Ceruloplasmin

“…Previous studies from these laboratories have shown that inorganic cobalt [7], as well as a number of other inorganic metals [14][15][16] and organometallic compounds [4,[17][18][19] are capable of producing changes in the activities of the enzymes that control heme biosynthesis and degradation. Among the organometallic compounds that have been demonstrated to possess these properties, cobalt-protoporphy rin is unique in exerting an extremely pro longed effect (up to 4 weeks after a single dose) on heme oxygenase induction in the liv er of treated animals [8], in comparison to its inorganic metal counterpart, cobalt chloride.…”