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

Abstract

Heme oxygenase (decyclizing) [heme, hydrogen-donor:oxygen oxidoreductase (.alpha.-methene-oxidizing, hydroxylating), EC 1.14.99.3] is greatly induced in the kidney by the administration of Ni or Sn. Mn, when administered simultaneously with Ni or Sn 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 h with Mn, the level of induction of heme oxygenase by Ni or Sn was markedly reduced in a time-dependent fashion. Mn treatment after the inducing metal was relatively ineffective in preventing the induction of heme oxygenase. Mn in vitro did not inhibit heme oxygenase in the microsomes isolated from either control or Sn-induced rats and in vivo did not increase the rate of catabolism of the induced enzyme. Mg was unable to block Ni or Sn induction of heme oxygenase. Zn in equimolar amounts could also substantially reduce the extent of induction of renal heme oxygenase when administered simultaneously with Ni or Sn. In addition, simultaneous Zn administration blocked, to a considerable extent, the induction of hepatic heme oxygenase by Ni, Co, or Cd. Metal-metal interactions may exist that can greatly influence the regulatory mechanism for the induced synthesis of heme oxygenase, the rate-limiting enzyme in heme degradation.