Protective Effect of Tyrosol and S-Adenosylmethionine against Ethanol-Induced Oxidative Stress of Hepg2 Cells Involves Sirtuin 1, P53 and Erk1/2 Signaling

Abstract

Oxidative stress plays a major role in ethanol-induced liver damage, and agents with antioxidant properties are promising as therapeutic opportunities in alcoholic liver disease. In the present work, we investigated the effect of S-adenosylmethionine (AdoMet), Tyrosol (Tyr), and their combination on HepG2 cells exposed to ethanol exploring the potential molecular mechanisms. We exposed HepG2 cells to 1 M ethanol for 4 and 48 h; thereafter, we recorded a decreased cell viability, increase of intracellular reactive oxygen species (ROS) and lipid accumulation, and the release into culture medium of markers of liver disease such as triacylglycerol, cholesterol, transaminases, albumin, ferritin, and homocysteine. On the other hand, AdoMet and Tyrosol were able to attenuate or antagonize these adverse changes induced by acute exposure to ethanol. The protective effects were paralleled by increased Sirtuin 1 protein expression and nuclear translocation and increased ERK1/2 phosphorylation that were both responsible for the protection of cells from apoptosis. Moreover, AdoMet increased p53 and p21 expression, while Tyrosol reduced p21 expression and enhanced the expression of uncleaved caspase 3 and 9, suggesting that its protective effect may be related to the inhibition of the apoptotic machinery. Altogether, our data show that AdoMet and Tyrosol exert beneficial effects in ethanol-induced oxidative stress in HepG2 cells and provide a rationale for their potential use in combination in the prevention of ethanol-induced liver damage.

Novel immunoassays to detect methionine adenosyltransferase activity and quantify S‐adenosylmethionine

“…The results reported in Tables suggested that SAM and/or SAM/SAH play important roles in the malignant transformation, proliferation, and apoptosis of liver cells; these findings are consistent with other reports . Therefore, SAM level could be a critical switch in the regulation of hepatocyte proliferation, regeneration, and response to injury .…”

NOX4/ROS mediate ethanol‑induced apoptosis via MAPK signal pathway in L‑02 cells

“…Ethanol-induced apoptosis is likely to be mediated via multiple pathways. For instance, ethanol elevates the expression levels of p53, which boosts apoptosis in HepG2 cells via the apoptotic pathway mediated by p53 (40). In addition, ethanol augments the activities of caspase-8 and caspase-9 in HepG2 cells, thereby mediating apoptosis by means of extrinsic and intrinsic pathways (41).…”

Artesunate induces ROS-dependent apoptosis via a Bax-mediated intrinsic pathway in Huh-7 and Hep3B cells

“…5D) in p53-null Hep3B cells supports this notion that p53 is a crucial promoter of ARS-induced cytotoxicity in HCC cells. Previous publications have demonstrated that p53 plays important but context-dependent roles in regulating cellular oxidative stresses, and antioxidant activities of p53 assist the survival of cells in response to low levels of oxidative stress while the pro-oxidative activities of p53 induce apoptosis of cells in response to high levels of oxidative stress [60][61][62]. Therefore, it is reasonable to suspect that p53 may increase cell death under circumstances where ROS is the preferential dominator in ARS-induced cytotoxicity.…”