Cytotoxicity of chloroquine in isolated rat hepatocytes

Abstract

Chloroquine is a synthetic quinoline being used as an antimalaria and antirheumatoid agent. Several cases of hepatotoxicity have been reported with the use of chloroquine. However, the mechanism(s) of its hepatotoxic effect is unknown. The purpose of this study was to investigate the cytotoxic mechanism of chloroquine. Cytotoxicity was studied using freshly isolated rat hepatocytes incubated in Krebs-Henseleit buffer under a flow of 95% O(2) and 5% CO(2). Chloroquine was toxic towards hepatocytes and caused cell death with an ED(50) of about 100 mm in 2 h. The events before cell death were rapid GSH depletion and lipid peroxidation. Cytochrome P-450 inhibitors, troleandromycine, cimetidine and quinidine increased the cytotoxicity of chloroquine. Antioxidants significantly prevented the cytotoxicity of chloroquine. Depleting the hepatocyte GSH beforehand increased the chloroquine cytotoxicity. Preventing chloroquine metabolism by specific P-450 inhibitors increased its toxicity, suggesting that a major part of its toxicity is mediated by chloroquine and not by its metabolites. A depletion of the antioxidant defense system is involved in the mechanism of cytotoxicity.

Development of a New Generation of 4-Aminoquinoline Antimalarial Compounds Using Predictive Pharmacokinetic and Toxicology Models

“…Numerous studies have reported hepatotoxicity resulting from use of CQ 19, 20. Therefore, we decided to screen our five lead candidates for any potential hepatotoxicity in our final stage of ADMET screening (Figures 4a and 4b).…”

Cytoprotective Effects of Taurine Against Toxicity Induced by Isoniazid and Hydrazine in Isolated Rat Hepatocytes

“…Hepatocyte viability was assessed by plasma membrane disruption as determined using the Trypan blue uptake test (24). Cell viability was determined immediately after isolation and at scheduled time intervals following incubation.…”

“…After treating a 1.0 mL aliquot of hepatocyte suspension (10 6 cells mL -1 ) with TCA (70 %) and boiling the supernatant with TBA (0.8 %) for 20 min, the absorbance of developed colour was measured at 532 nm in an Ultrospec2000 ® spectrophotometer (Pharmacia Biotech, Cambridge, England) (24).…”

Concurrent Inflammation Augments Antimalarial Drugs-Induced Liver Injury in Rats

“…Some investigations indicated the role of reactive metabolites and oxidative stress in chloroquine-induced liver injury. [11][12][13][14] Bioactivation of amodiaquine to a quinone imine metabolite, 15 and oxidative stress have also been suggested to be involved in the development of amodiaquine-induced hepatotoxicity. 16,17 Drug-inflammation interaction is an intriguing model for investigating the mechanisms of drug-induced liver injury.…”