الفهرس 
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Abstract
Paracetamol is a highly utilized over- the- counter analgesic drug that is extensively utilized worldwide. Although it is found to be safe at therapeutic doses, it can cause significant morbidity and mortality at higher doses, especially in individuals with pre-existing liver disease.
At the therapeutic doses, the amount of NAPQI formed by the cytochrome P450 is immediately detoxified by reaction with reduced glutathione (GSH), however in overdose situations, NAPQI occurs at amounts that exceed the body detoxification capacity leading to glutathione depletion, free radical formation, increased oxidative stress, reduced the antioxidant defense mechanisms and cell damage.
Glutathione S-transferase A1 (GSTA1) is an important enzyme for detoxification and cyto-protection as it can stimulate the conjugation of NAPQI and oxidative stress products to glutathione in order to be excreted in non-toxic way. It is used as a biomarker that predicts hepatic injury; as it is released in serum in association with hepatocyte necrosis, it is more sensitive and earlier predictor than alanine aminotransferase.
Dexmedetomidine (DEX) is a potent and specific α2 receptor agonist with sedative, anxiolytic and analgesic effects. DEX has anti- inflammatory and antioxidant effects, and is shown to reduce ischemia and reperfusion injury, it is known to activate pro-survival kinases and endothelial nitric oxide synthesis, modifying oxidative and inflammatory responses.
The current study was conducted to assess the effectiveness of Glutathione S- transferase A1 as an early biomarker for acetaminophen induced hepatotoxicity. In addition, to assess whether dexmedetomidine has an injury-reducing effect on liver and kidney induced by acute APAP toxicity experimentally in rates.
One hundred male albino rats with average weight 200-250 grams were involved in this study. The animals were divided into five groups, 20 rodents per each group and they were arranged as follows:
group (I): The control group. Rats were received saline by oral route through orogastric tube to exclude stressful condition.
group (II): Rats were received 1g/kg paracetamol diluted in 3ml volume of 0.9 % NaCl via gavage.
group (III): Rats were received 400mg/kg N- acetylcysteine (NAC) by intra peritoneal injection 1 hour after administration of the same APAP dose.
group (IV): Rats were received 100 μg/kg dexmedetomidine (DEX) by intra peritoneal injection 1 hour after the same APAP dose.
group (V): Rats were simultaneously received both 100 μg/kg DEX and 400 mg/kg NAC by intra peritoneal injection after the same APAP dose.
Blood samples were taken from rats in group (II) at 6, 8 and 10 hours post drug intake. Then blood samples were collected 24 hours after saline intake in rats of group (I) and after intake of drugs in the other examined groups. Liver and kidney were carefully dissected and prepared for histopathological studies.
The results of the study revealed that regarding to the effect of paracetamol toxicity on liver enzymes, there was a significant increase in ALT and AST levels in groups received APAP while there were significant reduced levels in groups received the antioxidant and DEX; (APAP and NAC), (APAP and DEX) and (APAP, NAC and DEX).
Histopathological examination of liver tissues obtained from rats receiving APAP revealed disruption of the normal hepatic architecture in the form of centrilobular hepatic necrosis, hepatocytic vacuolization, dilatation and congestion of the central veins and sinusoids with large number of infiltrating neutrophils and monocytes were seen in the portal tracts, while the liver tissues obtained from rats receiving (APAP and NAC) and (APAP, NAC and DEX) showed a significant decrease in hepatocytes degeneration, dilated congested central vein and sinusoids. Liver tissues obtained from DEX group showed significant improvement in liver histopathological score in the form of less apoptotic and necrotic hepatocytes with mild inflammatory cellular infiltration compared to APAP group.
Glutathione S-transferase A1 increased significantly 6 hours post APAP ingestion while ALT and AST were still at the baseline and starting to increase significantly 8 hours post ingestion, so it has a greater diagnostic potential for acetaminophen induced liver injury compared to ALT and AST.
Regarding the results of the effect of paracetamol toxicity on renal function, there was a significant increase in urea and creatinine levels in groups received APAP while there were significant reduced levels in groups received the antioxidant and DEX; (APAP and NAC), (APAP and DEX) and (APAP, NAC and DEX).
Histopathological examination of kidney tissues obtained from rats receiving APAP and (APAP and DEX) revealed significant increase in the histological scoring indicates tubular injury with vacuolization and epithelial degeneration. Also glomerular sclerosis with congested blood vessels with large number of infiltrating inflammatory cells were seen in the renal cortex. While the kidney tissues obtained from rats receiving (APAP and NAC) and (APAP, NAC and DEX) showed a significant decrease in the histological scoring when compared to the APAP group with marked reduction in the extent of proximal tubular necrosis and the degree of glomerulosclerosis.
MDA level showed significant increase in rats received APAP and significant reduced levels in the whole other examined groups compared to the APAP group, however, MDA in DEX administered group was still showing significant increased level but much lower than (improved) its level in APAP administered group.
The study revealed that regarding to GSH-Px, there was a significant decrease in its level in the APAP group if compared with the whole other examined groups which showed significant increased levels.
As regard catalase levels, the study showed a significant reduction in its level in the APAP group if compared with the whole other examined groups, groups administered (APAP and NAC) and (APAP, DEX and NAC) showed significant increase in catalase levels while the DEX administered group didn’t show the significant increased level.
The study revealed that regarding the effect of DEX administration on the histopathological results, it was shown that although there was a well observed histopathological improvement of the liver tissues obtained from rats receiving (APAP and DEX), there was no similar improvement in the histological scores of kidney tubular injury. This indicates the consideration that there may be a different mechanism of renal injury still has to been found out.