Children's toxicology from bench to bed - Liver Injury (3): Oxidative stress and anti-oxidant systems in liver of patients with wilson disease

Abstract

-The role of oxidative stress in the pathogenesis of liver disease in Wilson disease (WD), a genetic disorder characterized by excess hepatic deposition of copper, which generates free radicals, remains unclear. This study investigates oxidative stress on the liver and hepatic anti-oxidant responses in WD using liver specimens from affected patients showing mild liver damage (group I, n = 3), moderate or greater liver damage (group II, n = 5) and fulminant hepatic failure (group III, n = 5), and from asymptomatic carriers (n = 2). Decreased ratios of reduced glutathione (GSH) to oxidized glutathione (GSSG) and increased thiobarbituric acid reactive substance (TBARS), a lipid peroxidation product, were found in every affected patient, especially in groups II and III patients. Activities and protein expressions of Mn-dependent superoxide dismutase (Mn-SOD), CuZn-SOD, and catalase were decreased in all patients, especially in group III patients. Glutathione peroxidase activity was decreased only in group III patients. Asymptomatic carriers without any clinical manifestations showed normal TBARS level and GSH/GSSG ratio with increases in both GSH and GSSG levels. Their CuZn-SOD, Mn-SOD and catalase activities were increased. These results suggest that excessive copper-derived oxidants contribute to development and progression of liver disease in WD.

Decreased serum antioxidant capacity in patients with Wilson disease is associated with neurological symptoms

“…As expected, we found a lower TAC in our patients with WD, most probably due to oxidative stress induced by accumulated copper (Videla et al 2003). This is consistent with decreased levels of different antioxidants (Sinha et al 2005), and increased oxidative stress (Nagasaka et al 2009, Ogihara et al 1995 previously reported. However, in none of these studies were differentiations performed between the hepatic or neurological forms of WD.…”

“…In fact, copperinduced free-radical formation, lipid peroxidation (Videla et al 2003), and subsequent oxidative damage of hepatocytes' mitochondria are reported to be crucial in WD pathogenesis (Sokol et al 1994). In fact, decreased levels of different antioxidants and increased oxidative stress (Nagasaka et al 2009, Ogihara et al 1995) have been described, using different methods, in patients with the hepatic presentation of WD (Nagasaka et al 2006). Experiments using HepG2 cells have shown that proteins involved in antioxidant defense are dramatically altered by chronic copper exposure (Jimenez et al 2002).…”

Is it time to reconsider current guidelines for copper content in commercial dog foods?

“…Copper-associated hepatic injury results in decreases in hepatic and plasma glutathione and vitamin E concentrations. 25,26,[31][32][33][34] Because de novo hepatic synthesis of glutathione is the predominant source of plasma glutathione and plays a vital role in glutathione homeostasis, copper-associated hepatic injury can have widespread systemic consequences (eg, exacerbation of oxidative injury caused by concurrent illnesses).…”

Clusterin (Apolipoprotein J), a Molecular Chaperone That Facilitates Degradation of the Copper-ATPases ATP7A and ATP7B

“…Oxidative Stress Promotes Clusterin Interaction with ATP7B-Clusterin activity is initiated in response to cellular stresses (17,20), and both copper excess and deficiency are known to cause oxidative stress in cells (31,32). To determine whether the interaction is modulated directly by oxidative stress, co-immunoprecipitation experiments were repeated using HepG2 cells treated with either H 2 O 2 (20 min) or diamide (15 min) (Fig.…”