ReviewProtective effects of nicotinamide against acetaminophen-induced acute liver injury
Highlights
► NAM has protective effects against acetaminophen-induced acute liver injury. ► The TNF-α, IFN-γ and IL-6 levels were markedly increased after APAP exposure. ► The anti-inflammatory action may be involved in protective effects of NAM.
Introduction
Acute liver failure is a global disease, which results from a variety of liver lesions. The major causes of acute liver failure are viral infections, drug exposure, ethanol, accidental food poisoning and radiation damage [1], [2], [3]. In recent years the incidence of drug-induced liver injury has increased. It has become the leading cause of acute liver failure in the United States, contributing to approximately half of all cases [1], [4]. Therefore, it is urgent to develop a new effective drug to prevent and treat the drug-induced liver injury.
Overdose of acetaminophen (APAP) is widely used as an analgesic and antipyretic agent known to induce liver injury, accounting for the most frequent form of acute liver failure in the United States and many European countries [1]. In addition, accidental or intentional intake of an overdose of APAP often causes acute hepatocellular necrosis with high morbidity and mortality [5], [6]. It is generally accepted that the major toxicity of APAP is induced by cytochrome P450-mediated formation of hepatotoxic adducts N-acetyl-p-benzoquinoneimine (NAPQI), a highly reactive electrophilic molecule. NAPQI could cause harm by formation of covalent bonds with other intracellular proteins, which is influenced by several factors such as inflammatory responses, cytokine production, and hepatocyte apoptosis [7], [8], [9].
Nicotinamide (NAM) is the amide form of vitamin B3, which is synthesized from nicotinic acid and obtained through dietary source [10]. NAM has important biological function and the deficiency of it may lead to pellagra [11]. Over the years, NAM has been used to treat various diseases such as pellagra, and some studies also indicate that it is beneficial to psoriasis, schizophrenia, and type I diabetes [12], [13]. Recently, it has been shown that NAM exerts the anti-inflammatory properties both in vitro and in vivo. In this context, treatment with NAM resulted in a significant reduction of the synthesis of pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1), and the expression of inducible nitric oxide synthase (iNOS) in immune cells. In a mouse model of endotoxin-induced lung inflammation, NAM decreased the levels of cellular and biochemical inflammation markers [14]. In addition, NAM provided protective benefits in inflammation-based disorders, such as lethal endotoxemia and polymicrobial sepsis [15]. Despite these encouraging advances, the functional role of NAM in APAP-induced acute liver failure, an inflammation-driven life-threatening illness, remains largely unknown. Here, we provide solid evidence that NAM exerts protective effects on APAP-induced acute liver injury in mice.
Section snippets
Animals
Six-week-old male Balb/c mice weighing 20–25 g were obtained from the Experimental Animal Center of Chongqing Medical University, and were given a standard laboratory diet and water ad libitum. All mice were maintained under specific pathogen-free conditions at a temperature of 20–25 °C, 50 ± 5% relative humidity under a 12 h dark/light cycle, and acclimatized for at least l week before use. All experimental procedures involving animals were approved by the Animal Care and Use Committee of Chongqing
Effects of pretreatment with NAM on plasma ALT and AST levels
The circulating levels of hepatic enzymes AST and ALT are widely used as biochemical markers for evaluation of hepatic injury. The prophylactic effects of NAM given 30 min prior to a toxic dose of APAP, on plasma ALT and AST levels are shown in Fig. 1. As expected, administration of APAP markedly increased plasma ALT and AST levels to 2334.4 ± 110.8 U/L from 318.3 ± 16.7 U/L in controls, respectively. Interestingly, plasma ALT and AST levels in mice pretreated with NAM were significantly decreased by
Discussion
In the present study, we investigated the protective effects of NAM on APAP-induced liver injury in mice. APAP at overdose level could induce lethal fulminant hepatitis in mice [19]. Using this model, we found that pretreatment with NAM significantly improved the survival rate of mice with APAP-induced liver injury. The improved survival rate was accompanied with alleviated elevation of plasma aminotransferase and attenuated histopathological lesions in APAP-induced liver injury in mice with
Acknowledgments
This work was supported by the grants from the Chongqing Science & Technology Commission (no. cstc2011 lljjA10020 and cstc2009BB5064) and the National Nature Science Foundation of China (no. 30900651).
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Contributed equally.