Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver through α-Adrenergic Signaling.

In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4 induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4 induced lipid peroxidation and hepatotoxicity were suppressed by administration of an α-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepatic α-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.

Role of the sympathetic nervous system in carbon tetrachloride-induced hepatotoxicity and systemic inflammation.

Carbon tetrachloride (CCl4) is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS) in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL)-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor-α (TNF-α)], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response.

Protective effects of kaempferol on isoniazid- and rifampicin-induced hepatotoxicity.

Isoniazid (INH) and rifampicin (RIF) are the first-line drugs for antituberculosis (anti-TB) chemotherapy. The levels of serum transaminases [aspartate aminotransferase (AST) and alanine aminotransferase (ALT)] are abnormal in 27% of patients undergoing INH and RIF treatments and in 19% of patients undergoing treatment with INH alone. Cytochrome P450 2E1 (CYP2E1) metabolizes many toxic substrates, including ethanol, carbon tetrachloride, and INH, which ultimately results in liver injury. The objective of this study was to screen for CYP2E1 inhibitors in vitro and investigate whether the selected compound could prevent INH/RIF-induced hepatotoxicity in vivo. We screened 83 known compounds from food and herbal medicines as inhibitors of CYP2E1. The hepatotoxic dose of INH/RIF was 50/100 mg kg(-1) day(-1). Hepatotoxicity was assessed using galactose single-point (GSP) method (a quantitative measurement of liver function), histopathological examination of the liver, malondialdehyde (MDA) assay, and measurement of AST and ALT activities. Kaempferol inhibited CYP2E1 activity in mice by 0.31- to 0.48-fold (p < 0.005). Mice with INH/RIF-induced hepatotoxicity showed significantly abnormal serum levels of AST and ALT, and GSP value, and these values could be decreased by the administration of kaempferol (p < 0.005). Kaempferol significantly reduced the depletion of hepatic glutathione and prevented the increase in MDA formation in mice. Furthermore, kaempferol did not affect the anti-TB effects of INH/RIF. To our knowledge, this is the first report of kaempferol's utility as an adjuvant for preventing CYP2E1-mediated hepatotoxicity induced by drugs such as INH and RIF.

Hepatitis, gallbladder hydrops, splenomegaly, and ascites in a child with scarlet fever.

We report a case of scarlet fever associated with hepatitis, gallbladder hydrops, splenomegaly, and ascites in a 15-year-old girl. The girl presented with fever and skin rash. Leukocyte, liver enzyme, and serum C-reactive protein concentrations were elevated. Ultrasonography revealed marked gallbladder wall thickening, diffuse liver parenchymal disease with moderate splenomegaly, and moderate ascites throughout the abdominal and pelvic cavities. Blood cultures for group A ß-hemolytic streptococci were negative. Complete recovery was facilitated with antibiotic treatment.

Effects of hyperglycemia on quantitative liver functions by the galactose load test in diabetic rats.

Blood galactose clearance after an intravenous galactose load has been widely used as a quantitative liver function test. We have developed a novel quantitative rat liver function test, the galactose single point (GSP) method, to assess residual liver function with various injuries by measuring single time point galactose concentration in blood after an intravenous bolus injection of galactose. The goal of this study was to evaluate the influence of nonhepatic factors such as hyperglycemia on GSP and galactose elimination capacity (GEC) in rats. Four groups of animal studies were carried out, as follows: (1) normal control (NC), (2) streptozotocin-induced diabetes (DM), (3) carbon tetrachloride-induced hepatotoxicity (CCl(4)), and (4) streptozotocin-induced diabetes with CCl(4)-induced hepatotoxicity (DM + CCl(4)). The serum glucose levels in the diabetic groups (DM and DM + CCl(4)) were significantly increased compared with the NC and CCl(4) groups (P < .001). A significant increase in hepatic activities of aspartate aminotransferase and alanine aminotransferase was observed in the CCl(4)-treated groups (CCl(4) and DM + CCl(4)) compared with the NC and DM groups (P < .001). In comparison with the NC group, the values of GSP and GEC in the diabetic groups (DM and DM + CCl(4)) were significantly reduced (P < .001) and increased (P < .01), respectively. Galactose single point had highly significant correlations with GEC (P < .001). These results suggest that galactose metabolism tests-as quantitative parameters of liver function-should be interpreted with caution in the condition of a significant hyperglycemia.