The role of heme oxygenase during the initiation stage of chemically induced hepatocarcinogenesis

CABALLERO, FABIANA; GEREZ, ESTHER; BATLLE, ALCIRA; VAZQUEZ, ELBA

Orlando, Florida

Congreso; Experimental Biology 2001; 2001

American Society for Biochemistry and Molecular Biology

Heme oxygenase (HO), consisting of two major isoforms: the inducible HO1 and the constitutive HO2, controls the heme degradation pathway leading to the production of antioxidant bilirubin and the second messenger CO and the release of prooxidant Fe2+. The stress inducible gene HO1 provides protection against oxidative stress. The anti-inflammatory properties of HO1 have also been demonstrated. The present study examines the modulation of HO in response to the oxidative damage during the initiation stage of hepatocarcinogenesis. CF1 mice were fed with p-dimethylaminoazobencene (DAB, 0.5% w/w) during a period of 28 weeks. Animals have been treated and sacrificed in conformance with the FASEB Statement of Principles for the use of animals in research. The overall HO activity was diminished during the first 10 weeks of treatment. Afterwards, activity was recovered and a 20% induction was reached from week 20th onwards. GSH content increased gradually along the treatment. Northern blot analysis revealed that HO1 was markedly induced (170%) in the liver of that treated animals. The induction of the genetic expression of HO1 could be ascribed to the oxidative damage provoked by the carcinogen which was confirmed by the significant enhancement of TBARS content (90% from week 2 to week 10; 200% from week 12 to week 28). Increased cytotoxicity was accompanied by a massive influx of neutrophiles into the tissue, reflecting the inflammatory process. This result suggest that HO1 might have a protective role against the damaging effect of radicals, the synthesis of HO would be induced as and adaptative cellular response, whereas the enzyme activity would be modulated by post transcriptional events.