S-allyl-glutathione improves experimental liver fibrosis by regulating Kupffer cell activation in rats.

Abstract

S-allyl-glutathione (SAG) is one of the metabolites of diallyl sulfide (DAS), a component of garlic. DAS has shown preventative effects on carcinogenesis in animal models. However, whether synthetic SAG can improve liver fibrosis has not been investigated. We examined the potential preventive effects of SAG on acute and chronic models of liver fibrosis by chronic carbon tetrachloride (CCl4) administration. SAG inhibited liver fibrogenesis induced by CCl4 in a dose-dependent manner and reduced heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers. In fibrosis regression models, after administration of either CCl4 for 9 wk or dimethyl nitrosamine (DMN) for 6 wk, SAG markedly accelerated fibrolysis in both models. In the regression stage of DMN-treated liver, SAG normalized the ratio of M2 phenotype (expression of mannose receptor) in Kupffer cells (KCs). Consistent with these results, the culture supernatants of SAG-treated M2-phenotype KCs inhibited collagen-α1(I) chain (COL1A1) mRNA expression in primary culture-activated rat hepatic stellate cells (HSCs). However, SAG did not directly inhibit HSC activation. In an acute model of CCl4 single injection, SAG inhibited hepatic injury dose dependently consistent with the inhibited the elevation of the bilirubin and ALT levels. These findings suggest that SAG could improve the fibrogenic and fibrolysis cascade via the regulation of excess activated and polarized KCs. SAG may also serve as a preventive and therapeutic agent in fibrosis of other organs for which current clinical therapy is unavailable. NEW & NOTEWORTHY S-allyl-glutathione (SAG) is a metabolite of diallyl sulfide, a component of garlic. SAG increased hepatic glutathione levels and GSH-to-GSSG ratio in normal rats. SAG treatment before or after liver fibrosis from chronic CCl4 administration improved liver fibrosis and regression. SAG decreased heat shock protein-47 (HSP47), a collagen-specific chaperone, and other fibrosis markers in CCl4-treated livers. SAG-treated Kupffer cell conditioned medium also inhibited collagen-α1(I) chain (COL1A1) mRNA expression and other markers in primary culture hepatic stellate cells.