Mechanism of hepatocarcinogenensis initiation: involvement of monooxygenases system

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

San Francisco, EEUU

Congreso; 1999 BIOCHEMISTRY AND MOLECULAR BIOLOGY JOINT MEETING; 1999

American Society of Biochemistry and Molecular Biology (ASBMB)

Most drugs and xenobióticos are lipid soluble compounds which needs to be transformed into more polar water soluble molecules by a system of hepatic monooxygenases, to be excreted. Cimetidine (CIM) inhibits hepatic mixed function oxydase activity. The aim of this study  was to investigate the possible preventive and / or reversal action of CIM on cytochrome P450 induction and other metabolic alterations provoked by the carcinogen p-dimethylaminoazobenzene (DAB). A group of male CF1 mice received a standard laboratory diet and other group was placed on dietary DAB (0.5% w/w). After 40 days of treatment, animals of both groups received DAB and two weekly doses of CIM (120 mg/kg ip) during the following 35 days. CIM prevented and reversed d-aminolevulinate synthetase induction provoked by DAB. The same effect was observed on cytochrome P450 content. However, it was found that CIM did not modify the decrease in heme oxygenase activity produced by DAB. The great increase in glutathione S-tranferase activity, a marker enzyme of liver damage, provoked by DAB, persisted in those animals then treated with CIM. This drug did not modify either the antioxidant defense system diminution (inferred by catalase activity). This results give further support to our hypothesis about the necessary multiple biochemical pathway disturbance for the onset of the initiation of hepatocarcinogenesis.