Interaction of cimetidine with P450 in a mouse model of hepatocarcinogenesis initiation

Abstract

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 pdimethylaminoazobenzene. A group of male CF1 mice received a standard laboratory diet and another group was placed on dietary p-dimethylaminoazobenzene (0.5% w w 71 ). After 40 days of treatment, animals of both groups received pdimethylaminoazobenzene and two weekly doses of cimetidine (120 mg kg 71 , i.p.) during a following period of 35 days. Cimetidine prevented and reversed d-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.

Ex vivo carbon monoxide prevents cytochrome P450 degradation and ischemia/reperfusion injury of kidney grafts

“…However, previous reports using CYP inhibitors such as cimetidine or piperonyl butoxide show that CYP degradation and detrimental heme/iron increase from the organ during I/R injury are inhibited by these drugs due to their binding to heme and CYP stabilization. 32,33 It is also known that hemoglobin becomes more stable and resistant against oxidative stress when oxygen binds to hemoglobin and forms oxyhemoglobin. 34 Although further studies will be necessary to confirm the actual binding site of CO, it is tempting to conceive that CO-binding to heme moiety of renal CYP could prevent CYP degradation and block heme/ iron release during kidney I/R injury.…”

Immunohistochemical analysis of heme oxygenase‐1 in preneoplastic and neoplastic lesions during chemical hepatocarcinogenesis§

“…Our results reveal and underline the importance of HO‐1 expression in normal tissue, and its up‐regulation suggests a cell‐protective response to the stress provoked by the generation of ROS during the carcinogen metabolism (Caballero et al . 2001; Caballero et al . 2002).…”

Inhibition of Drug Metabolizing Enzymes (Cytochrome P450) in Vitro as Well as in Vivo by Phyllanthus amarus SCHUM & THONN

“…These DNA adducts produce mutation and subsequent transformation of the normal cell to cancer cells. P450 system can be influenced by a number of exogenous and endogenous factors and its induction and inhibition is of the utmost interest in carcinogenesis 3) as well as the bioavailability and activity of the drug. CYP 1A1, 1A2, and 2B family activate certain promutagens such as benzopyrene (B (a) P) and other environmental pollutants metabolically to their ultimate carcinogenic form.…”