Protective effect of ghrelin on acetaminophen-induced liver injury in rat

Abstract

Ghrelin is a peptide that has protective effects on many tissues of the body. It has anti-inflammatory and anti-oxidant effects. Acetaminophen, a commonly used analgesic-antipyretic drug, has hepatotoxic side effects. The aim of this study was to evaluate the protective role of ghrelin in liver toxicity due to acetaminophen overdose. Thirty male rats were used in this study and divided into five groups. They were control, propylene-glycol (as a solvent of acetaminophen), acetaminophen, acetaminophen and NAC, acetaminophen and ghrelin groups. Tumor necrosis factor alpha (TNF-α), and hepatic enzymes, AST (aspartate aminotransferase) and ALT (alanine aminotransferase), were assessed and histologic study of liver were performed as indicators of liver damage following acetaminophen toxicity. Results showed that Ghrelin decreased ALT and AST to the normal level, and also reduced TNF-α. Although NAC (the standard antidote of acetaminophen toxicity) also reduced ALT, AST and TNF-α levels, our results show that ghrelin is more potent than NAC in protecting the liver from acetaminophen-induced liver injury.

Introduction

Acetaminophen or paracetamol, is a widely used analgesic and antipyretic drug throughout the world [21] and its toxicity is the most common cause of hepatic failure requiring liver transplantation [8]. In the United States, its toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure, and it is the second most common cause of liver failure requiring transplantation [8], [16].

Acetaminophen is metabolized primarily in the liver [28]; however, small amounts of it (about 4%) is metabolized via the hepatic cytochrome P450 enzyme system (CYP) to produce inactive sulfate and glucuronide conjugates [9], or to form a reactive and highly toxic metabolite known as N-acetyl-P-benzo-quinone imine (NAPQI). Then glutathione binds to NAPQI enabling it to be excreted as a nontoxic form in the urine [9].

Therapeutic doses of acetaminophen do not cause hepatic injury, but in acute overdose or when the maximum daily dose is exceeded over a prolonged period, the normal conjugation pathways of metabolism become saturated [13]; NAPQI cannot be detoxified and therefore reacts with cell membrane lipids, leading to hepatocellular damage [13].

The antidote for acetaminophen poisoning is N-acetyl cysteine (NAC) [23], which is a precursor of glutathione, so that it increases the available glutathione for conjugation with NAPQI. It also has anti-inflammatory and anti-oxidant effects. NAC increases local nitric oxide (NO) concentrations, causing a vasodilatory effect on microcirculation that enhances oxygen delivery to peripheral tissues [17].

NAC may cause side effects, including nausea, vomiting, flatus, diarrhea and gastroesophageal reflux and even anaphylactic shock [9]. Therefore, it is desirable to find a new treatment with fewer side effects and more potency than NAC.

Ghrelin is a newly discovered gut hormone, mainly produced in the stomach [1], but also identified in endocrine cells of the gastrointestinal tract [5].

Ghrelin plays a role in a number of different physiological processes. For example, it enhances growth hormone secretion [22] and increases appetite [22], regulates cell proliferation [27], stimulates prolactin and adrenocorticotrophic hormone [14], promotes slow wave sleep [24] and memory retention [4].

In the stomach, ghrelin affects gastric acid secretion and motility, and exhibits gastroprotective effect [3]. In mammals, ghrelin plays an important role in the immune system [26]. Exogenous ghrelin significantly inhibited the activation of Nuclear Factor-KappaB (NF-κB) and plasma tumor necrosis factor alpha (TNF-α) level [15].

The anti-oxidant and anti-inflammatory effects of ghrelin were previously demonstrated [7]. As the main mechanism of acetaminophen toxicity is via inflammation and oxidative stress, this study was designed to evaluate the possible protective effect of ghrelin in hepatocellular damage secondary to acetaminophen toxicity in rats.