Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation.
Many drugs and xenobiotics are lipophilic and they should be transformed into more polar water soluble compounds to be excreted. Cimetidine inhibits cytochrome P450. The aim of this study was to investigate the preventive and/or reversal action of cimetidine on cytochrome P450 induction and other metabolic alterations provoked by the carcinogen p-dimethylaminoazobenzene. A group of male CF1 mice received a standard laboratory diet and another group was placed on dietary p-dimethylaminoazobenzene (0.5% w w(-1). After 40 days of treatment, animals of both groups received p-dimethylaminoazobenzene and two weekly doses of cimetidine (120 mg kg(-1), i.p.) during a following period of 35 days. Cimetidine prevented and reversed delta-aminolevulinate synthetase induction and cytochrome P450 enhancement provoked by p-dimethylaminoazobenzene. However, cimetidine did not restore haem oxygenase activity decreased by p-dimethylaminoazobenzene. Enhancement in glutathione S-transferase activity provoked by p-dimethylaminoazobenzene, persisted in those animals then treated with cimetidine. This drug did not modify either increased lipid peroxidation or diminution of the natural antioxidant defence system (inferred by catalase activity) induced by p-dimethylaminoazobenzene. In conclusion, although cimetidine treatment partially prevented and reversed cytochrome P450 induction, and alteration on haem metabolism provoked by p-dimethylaminoazobenzene AB, it did not reverse liver damage or lipid peroxidation. These results further support our hypothesis on the necessary existence of a multiple biochemical pathway disturbance for the onset of hepatocarcinogenesis initiation.
Caballero
F
F
Centro de Investigaciones sobre Porfirinas y Porfirias (CIPYP) (CONICET - FCEN, UBA), Ciudad Universitaria, Pabellón II, 2do piso, C1428EHA Buenos Aires, Argentina.
Gerez
E
E
Batlle
A
A
Vazquez
E
E
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity; D002374:Catalase / Q000378:metabolism; D002927:Cimetidine / Q000378:metabolism* / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005982:Glutathione Transferase / Q000378:metabolism; D006418:Heme / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008297:Male; D051379:Mice; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D004124:p-Dimethylaminoazobenzene / Q000633:toxicity
D002273:Carcinogens; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D006418:Heme; D002927:Cimetidine; D003577:Cytochrome P-450 Enzyme System; D004124:p-Dimethylaminoazobenzene; D002374:Catalase; D000624:5-Aminolevulinate Synthetase; D005982:Glutathione Transferase