MECHANISM OF INDUCTION OF HEME OXYGENASE BY METALLOPORPHYRINS IN PRIMARY CHICK-EMBRYO LIVER-CELLS - EVIDENCE AGAINST A STRESS-MEDIATED RESPONSE

Heme oxygenase catalyzes the first and rate-controlling step in heme c atabolism. One of the two forms of heme oxygenase theme oxygenase-l) h as been shown to be increased by heme, metals, and in some systems, by certain environmental stresses. However, it remains uncertain whether heme induces hepatic heme oxygenase-l by a general stress response, o r a specific heme-dependent cellular response. The work communicated h ere explores this issue by examining possible mechanisms whereby heme and other metalloporphyrins induce heme oxygenase-l in normal liver ce lls. Primary cultures of chick embryo liver cells were tested for thei r ability to increase heme oxygenase mRNA after exposure to selected m etalloporphyrins (heme, chromium mesoporphyrin, cobalt protoporphyrin and manganese protoporphyrin), The ability of antioxidants to decrease metalloporphyrin-mediated induction of heme oxygenase-l mRNA was also tested. Our results indicate that: 1) the increase in heme oxygenase- l mRNA mediated by heme or other metalloporphyrins may involve a short -lived protein(s) since the increase was prevented by several inhibito rs of protein synthesis; and 2) in normal liver cells, heme-dependent oxidative stress does not play a key role in the heme-mediated inducti on of heme oxygenase-l. We conclude that heme and other non-heme metal loporphyrins induce heme oxygenase-1 through a mechanism requiring pro tein synthesis, not because metalloporphyrins increase cellular oxidat ive or other stress.