Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

Abstract

Caveolin-1 (Cav-1) is a membrane scaffolding protein which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1 −/− ) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild type mice with acetaminophen (300 mg/ kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1 −/− mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1 −/− mice is not due to alterations in anti-oxidant defense. In wild type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1 −/− mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1 −/− mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

Inhibitory effects of Schisandra chinensis on acetaminophen-induced hepatotoxicity

“…GSH is key in scavenging ROS (22). Consistent with the results of previous studies (23,24), acetaminophen intoxication resulted in reduced GSH levels in mice compared with those in the control group. Schisandra chinensis has been used in China, Korea and Japan to regulate various pathophysiological conditions, including hepatitis and cancer (6).…”

Role of STK in mouse liver macrophage and endothelial cell responsiveness during acute endotoxemia

“…Two major forms of the enzyme identified in the liver are cytosolic CuZnSOD and mitochondrial MnSOD [61]. The present studies show that acute endotoxemia up-regulates both isoforms of SOD in hepatic macrophages and endothelial cells and that this is dependent on STK.…”

New Insights into the Acetaminophen Hepatotoxicity Research

“…animal species also markedly influence the results: 24 hrs after APAP administration, PCNA expression is apparent in B6C3F1 mice [42] and B6J129 SVF2 mice [43], however, BrdU and PCNA (Invitrogen) methods only show negative or occasional positive staining in C57/BL6 mice [10,11,44]; more importantly, 48 hrs after APAP subjected to C57/BL6 mice, both PCNA (Invitrogen) and BrdU methods show that the extent of hepatic PCNA / BrdU expression depends mainly on the extent of liver damage, because the expression of hepatic PCNA /BrdU is significantly correlated with the area of hepatocyte necrosis for each mouse: larger size of necrosis has larger number of PCNA/BrdU positive cells, while improved liver repair with smaller necrotic size has smaller number of PCNA/BrdU positive cells, this is not conventionally expected [10,11,44]. In addition, the number of PCNA-positive non-parenchymal cells is 10 times larger than the number of BrdU-positive hepatocyte in C57/BL6 mice during APAP hepatotoxicity [11], suggesting that currently the nonparenchymal cells are likely underestimated, and the number of the non-parenchymal cell loss could be larger than the hepatocyte loss during APAP toxicity, the latter could explain the impaired immune function and the higher incidence of gram-negative infection during hepatotoxicity [11,45], further investigation is needed to focus on non parenchymal cell loss in APAP overdose.…”