Abstract
Background and Aims Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Part of phenacetin therapeutic activity is attributed to its metabolism into paracetamol. Paracetamol causes direct hepatic oxidative stress damage. 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. Methods 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. 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. Also histopathological examinations of liver tissues in various groups were done. Results 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. NAG and NAC significantly improve the PA- and PH-induced hepatic and blood, biochemical, and histopathological disturbances, respectively. Conclusions Both PA and PH induce oxidative stress in rat liver within their therapeutic doses. NAG and NAC in pharmacological doses can antagonize the oxidative damaging effect of both PA and PH.
Highlights
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 [1]
The overall results showed that both paracetamol and phenacetin cause disturbances in the liver architecture in the form of dilated congested central vein, deeply stained hepatocytic nuclei with vacuolated cytoplasm, and cellular infiltrations, with improvement of these changes approaching the control architecture in variable degrees among groups receiving antioxidants with the best notable improvement for PA-NAG group as regards paracetamol groups and for PHNAC group as regards phenacetin groups, which were in line with the biochemical analysis results
We choose in our study a rat model because PA-induced hepatic damage in rats resembles human liver damage, at both biochemical and histological levels [24]
Summary
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 [1] Both phenacetin (mostly due to its conversion to paracetamol) and paracetamol are hepatotoxic in animals [2]. 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. Both paracetamol (PA) and phenacetin (PH) are analgesic and antipyretic agents. Both PA and PH induce oxidative stress in rat liver within their therapeutic doses.
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