Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity: Expression of metallothionein and HSP70

• Published in: Biochemical pharmacology Vol. 66; no. 6; pp. 917 - 926
• Main Authors: Andrés, David, Sánchez-Reus, Isabel, Bautista, Mirandeli, Cascales, Marı́a
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15-09-2003; Elsevier Science
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Biotransformation; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Drug Interactions; Gadolinium - pharmacology; Gadolinium - therapeutic use; Gadolinium chloride; Gene Expression - drug effects; HSP70; HSP70 Heat-Shock Proteins - biosynthesis; Kupffer cells; Kupffer Cells - drug effects; Kupffer Cells - physiology; Male; Medical sciences; Metallothionein; Metallothionein - biosynthesis; Microsomes, Liver - metabolism; Mixed Function Oxygenases - metabolism; NADP - metabolism; Oxidative Stress - drug effects; Pharmacology. Drug treatments; Rats; Rats, Wistar; Thioacetamide - antagonists & inhibitors; Thioacetamide - toxicity; Thioacetamide hepatotoxicity; Thioacetamide hepatotoxicity; HSP70; Gadolinium chloride; Metallothionein; Kupffer cells; Depletion; Toxicity; Pharmacology
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(03)00443-X

Kupffer cell function plays an important role in drug-induced liver injury. Thus, gadolinium chloride (GD), by selectively inactivating Kupffer cells, can alleviate drug-induced hepatotoxicity. The effect of GD was studied in reference to metallothionein and heat shock proteins expression in an
in vivo model of liver necrosis induced by thioacetamide. Rats, pre-treated or not with GD (0.1
mmol/kg), were intraperitoneally injected with thioacetamide (6.6
mmol/kg), and samples of blood and liver were obtained at 0, 12, 24, 48, 72 and 96
hr. Parameters related to liver damage, Kupffer cell function, microsomal FAD monooxygenase activity, oxidative stress, and the expression of metallothionein and HSP70 were determined. GD significantly reduced serum myeloperoxidase activity and serum concentration of TNFα and IL-6, increased by thioacetamide. The extent of necrosis, the degree of oxidative stress and lipoperoxidation and microsomal FAD monooxygenase activity were significantly diminished by GD. The effect of GD induced noticeable changes in the expression of both metallothionein and HSP70, compared to those induced by thioacetamide. We conclude that GD pre-treatment reduces thioacetamide-induced liver injury and enhances the expression of metallothionein and HSP70. This effect, parallel to reduced levels of serum cytokines and myeloperoxidase activity, demonstrates that Kupffer cells are involved in thioacetamide-induced liver injury, the degree of contribution being approximately 50%.