HEME OXYGENASE AND OXIDATIVE STRESS - EVIDENCE OF INVOLVEMENT OF BILIRUBIN AS PHYSIOLOGICAL PROTECTOR AGAINST OXIDATIVE DAMAGE

Cobalt chloride (CoCl2), a well-known inducer of heme oxygenase, produ ced a strong increase of in vivo rat liver chemiluminescence (QLV) 6 h after its administration. The activity of antioxidant enzymes, supero xide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-P x) was found to be significantly decreased 9 h after CoCl2 injection. Heme oxygenase activity increased 9 h after treatment, reaching a maxi mum value around 18 to 24 h after CoCl2 administration. This induction was preceded by a decrease in the intrahepatic GSH pool and an increa se in hydrogen peroxide steady state concentration, both effects takin g place several hours before induction of the heme-oxygenase. Co-admin istration of Sn-protoporphyrin IX, a potent inhibitor of heme oxygenas e, completely prevented the enzyme induction, increasing the QLV level s. Administration of bilirubin, the end product of heme catabolism in mammals, prevented the heme oxygenase induction as well as the decreas e in hepatic GSH and the increase of chemiluminescence when it was adm inistered 2 h before CoCl2 treatment. These results support the propos al that the induction of heme oxygenase by cobalt chloride may be a ge neral response to oxidant stress and, by increasing bilirubin levels, could constitute an important cellular defense mechanism against oxida tive damage.