Methionine is also required for synthesis of cysteine which is the limiting amino acid for GSH synthesis. Methionine is an essential methyl donor in mammals and acts as an efficient scavenger of several oxidizing molecules. N-acetyl-L-methionine (NAM) is capable of replacing the dietary requirements for methionine. In addition to its indirect antioxidant effect (through incorporation in GSH formation), NAC exhibits also direct antioxidant properties through the interaction of its free thiol group with the electrophilic groups of ROS. N-acetylcysteine (NAC) is a precursor of the amino acid L-cysteine which is a component of the biologic antioxidant glutathione (GSH). Many studies prove the antioxidant properties of N-acetyl cysteine, N-acetyl methionine, and N-acetyl glucosamine. Acetaminophen is converted N-acetyl-p-benzoquinone imine (NAPQI) as an intermediate toxic metabolic product via cytochrome P450, which is nullified in the liver via binding to nonprotein sulfhydryl reduced glutathione (GSH) resulting in direct hepatic oxidative stress damage due to depletion of the antioxidant capacity (glutathione peroxidase) of the liver. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol. Phenacetin was replaced by the metabolite paracetamol (acetaminophen) which is nowadays one of the most commonly used antipyretic and analgesic drugs, and one of the well-known experimental models of hepatotoxicity. Phenacetin was extensively used as an analgesic and fever-reducing agent for many years however, its use was prohibited in the late 1970s due to its potential to cause renal nephropathy. Both phenacetin (mostly due to its conversion to paracetamol) and paracetamol are hepatotoxic in animals. Liver is frequently exposed to metabolic insults due to its major role in metabolism and detoxification of endogenous and exogenous compounds including drugs and xenobiotics. NAG and NAC in pharmacological doses can antagonize the oxidative damaging effect of both PA and PH. Both PA and PH induce oxidative stress in rat liver within their therapeutic doses. NAG and NAC significantly improve the PA- and PH-induced hepatic and blood, biochemical, and histopathological disturbances, respectively. PA and PH cause significant increase in hepatic levels of MDA, NO, and AFP and serum ALT, AST, and 8-OH-Gua levels, with significant decrease in hepatic GSH and total thiols. Also histopathological examinations of liver tissues in various groups were done. Biochemical assays of malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), total thiols, and alpha-fetoprotein (AFP) in liver homogenates and serum assays of ALT, AST, 8-hydroxy guanine (8-OH-Gua), and AFP were done. 90 male Wistar albino rats (120-140 gm) were undertaken, categorized randomly into 9 groups of 10 rats each, and administered by gavage for 2 weeks with DMSO 1% (controls), PA, PA+NAC, PA+NAM, PA+NAG, PH, PH+NAC, PH+NAM, and PH+NAG. The present study aimed to investigate the possible damaging effects of both PA and PH, when used in therapeutic doses, on rat liver and to compare the antioxidant and hepatoprotective effects of N-acetylcysteine (NAC), N-acetyl-methionine (NAM), and N-acetylglucosamine (NAG) against PA- or PH-induced hepatic damage. ![]() ![]() Paracetamol causes direct hepatic oxidative stress damage. ![]() Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents.
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