Depletion of Kupffer cell function by gadolinium chloride attenuates thioacetamide-induced hepatotoxicity. Expression of metallothionein and HSP70.
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 TNF alpha 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%.
Andrés
David
D
Facultad de Farmacia, Instituto de Bioquímica (CSIC-UCM), Ciudad Universitaria, Plaza de Ramón y Cajal sn, 28040 Madrid, Spain.
Sánchez-Reus
Isabel
I
Bautista
Mirandeli
M
Cascales
María
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001711:Biotransformation; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control; D004347:Drug Interactions; D005682:Gadolinium / Q000494:pharmacology* / Q000627:therapeutic use; D015870:Gene Expression / Q000187:drug effects*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D007728:Kupffer Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide / Q000037:antagonists & inhibitors* / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D018840:HSP70 Heat-Shock Proteins; D013853:Thioacetamide; D009249:NADP; D008668:Metallothionein; D005682:Gadolinium; D006899:Mixed Function Oxygenases; C038958:gadolinium chloride