Xanthine oxidase-derived reactive oxygen metabolites contribute to liver necrosis: protection by 4-hydroxypyrazolo[3,4-d]pyrimidine

Abstract

Xanthine oxidase (XO) generates reactive oxygen metabolites (ROM) as a by-product while catalyzing their reaction. The present study implicates these ROM in the pathogenesis of liver necrosis produced in rats by the intraperitoneal administration of thioacetamide (TAA; 400 mg/kg b.wt.). After 16 h of TAA administration, the activity of rat liver XO increased significantly compared to that of the control group. At the same time, the level of serum marker enzymes of liver necrosis (aminotransferases and alkaline phosphatase) and tissue malondialdehyde content also increased in TAA treated rats. Tissue malondialdehyde concentration is an indicator of lipid peroxidation and acts as a useful marker of oxidative damage. Pretreatment of rats with XO inhibitor (4-hydroxypyrazolo[3,4-d]pyrimidine; allopurinol (AP)) followed by TAA could lower the hepatotoxin-mediated rise in malondialdehyde level as well as the level of marker enzymes associated with liver necrosis. The survival rate also increased in rats given AP followed by the lethal dose of TAA. In either case, the effect of AP was dose-dependent. Results presented in the paper indicate that increased production of XO-derived ROM contributes to liver necrosis, which can be protected by AP.

Allopurinol Ameliorates Thioacetamide-Induced Acute Liver Failure by Regulating Cellular Redox-Sensitive Transcription Factors in Rats

“…XO is thought to be one the most important source of ROS [25,26]. TAA generates liver damage by upregulating hepatic XO activity [2]. This feature of TAA makes it a proper hepatotoxic agent for testing the effects of XO inhibition [3].…”

“…Despite technological advances and improvement in intensive care conditions, ALF continues to be one of the most challenging problems in clinical practice [1]. In various liver injury models [2][3][4][5], it has been revealed that increased xanthine oxidase (XO) activity plays pivotal role in the oxidative stress-induced hepatic damage. XO is widely distributed throughout various tissues with the highest level in the liver [6,7].…”

“…XO is widely distributed throughout various tissues with the highest level in the liver [6,7]. XO-derived oxidative stress-induced tissue damage may develop in various ways such as DNA damage by reactive oxygen species (ROS) [2], activation of NF-κB signaling pathway, and severe inflammatory cell infiltration [8]. Thioacetamide (TAA) has also been demonstrated to cause liver injury by increased XO-derived ROS formation [3,7].…”

Therapeutic Effects of Xanthine Oxidase Inhibitors: Renaissance Half a Century after the Discovery of Allopurinol

“…These models include various forms of liver injury, i.e., ones induced by ionizing radiation (Srivastava and Kale, 1999;Srivastava et al, 2002), ethanol (Oei et al, 1982;Lieber, 1997;Kono et al, 2000;Zima et al, 2001), cocaine (Aoki et al, 1997), thioacetamide (Ali et al, 2001), acetaminophen (Knight et al, 2001), and aluminum (Moumen et al, 2001). In the case of ethanol, aluminum, and radiation, enhancement of hepatic XO levels and/or spillage of XO into the circulation were detected (Oei et al, 1982;Zima et al, 1993;Moumen et al, 2001;Srivastava et al, 2002).…”

Signal transduction via the NF‐κB pathway: a targeted treatment modality for infection, inflammation and repair

“…They are also released from macrophages in response to bacterial invasion, and are generated as by-product during the enzyme catalysed reactions. 52,53 NF-B activation is associated with free radical generation and precedes, for example, pathological liver injury in experimental alcoholic liver diseases. 54 The viral protein NS5A, which activates NF-B, is observed to alter intracellular [Ca 2þ ] and induce oxidative stress.…”