Hepatoprotective effects of S‐adenosylmethionine and silybin on canine hepatocytes in vitro

Abstract

Inflammation and oxidative stress are associated with liver injury and development of liver disease. The transcription factors nuclear factor-kappa beta (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2) play critical roles in modulating liver injury and damage. Activation of NF-κB induces production of pro-inflammatory molecules including prostaglandin E2 (PGE2 ), interleukin-8 (IL-8) and macrophage chemotactic protein-1 (MCP-1). Nrf2 regulates genes controlling antioxidants. Our laboratory previously showed that hepatocytes, the primary functional cell type comprising liver tissue, respond to the cytokine interleukin-1 beta (IL-1β) by increased production of PGE2 , IL-8 and MCP-1. This increase is associated with nuclear translocation of NF-κB. In this study, we evaluated whether primary canine hepatocytes pre-treated with the combination of S-adenosylmethionine (SAMe; 30 and 2000 ng/ml) and silybin (SB; 298 ng/ml), agents with known anti-inflammatory and antioxidant properties, could attenuate IL-1β-induced inflammation and oxidative stress. The SAMe and SB combination reduced cytokine-induced PGE2 , IL-8 and MCP-1 production while also inhibiting NF-κB nuclear translocation. These changes were accompanied by increased antioxidant enzyme-reduced glutathione (GSH) comparable to control levels. The study shows for the first time that the SAMe and SB combination inhibits both inflammation and oxidative stress through two separate signalling pathways.

Protective effects of S-adenosylmethionine (SAMe) and silybin on hepatorenal and hemostatic functions in dogs with endotoxemia

“…Hepatorenal injury was characterized by increasing serum ALT, ALP, BUN, and Cr levels after LPS administration (Table 3). Our observations expanded the findings of the previous study, which was performed in vitro on canine hepatocytes (18), by demonstrating the protection of both liver and renal injuries in response to LPS in in vivo conditions. A possible mechanism is that SAMe and silybin in combination could inhibit the inflammation and oxidative stress that are associated with liver injury and development of liver diseases (18).…”

“…Our observations expanded the findings of the previous study, which was performed in vitro on canine hepatocytes (18), by demonstrating the protection of both liver and renal injuries in response to LPS in in vivo conditions. A possible mechanism is that SAMe and silybin in combination could inhibit the inflammation and oxidative stress that are associated with liver injury and development of liver diseases (18). Our previous studies showed that oxidative stress inhibition by choline treatment resulted in decreased sepsis severity and good prognosis in dogs with endotoxemia (27).…”

“…These positive effects of SAMe and silybin may be associated with attenuated IL-1β-induced inflammation and oxidative stress, as well as reduced cytokine-induced PGE2, IL-8, and macrophage chemotactic protein-1 production (18). Another possible mechanism may be that SAMe and its metabolite methylthioadenosine inhibit LPS-induced TNF-α expression by blocking the binding of LPS to histone-3, a TNF-α promoter (28), and increase liver levels of glutathione, an important compound for liver health (19).…”

“…Thus, liver protection in the course of sepsis is crucial to decrease mortality (16,17). Recent studies showed that S-adenosylmethionine (SAMe) and silymarin could prevent liver injury in different clinical conditions (toxininduced hepatopathy and alcohol-induced hepatopathy) (17) by regulating cytokine responses to the primary insult (18). SAMe is a compound that functions widely in the body as a group donor or enzymatic inducer during transmethylation, transsulfuration, and aminopropylation (17).…”

“…SAMe is a compound that functions widely in the body as a group donor or enzymatic inducer during transmethylation, transsulfuration, and aminopropylation (17). The liver synthesizes the majority of SAMe in the body (17), and SAMe has been shown to be an important compound for liver health (17)(18)(19).…”