Effect of the long-term use of a NOAEL dose of acetaminophen (paracetamol) on hepatic, renal, and neural tissues of aged albino rats

Abstract

Background: Paracetamol is one of the most popular drugs; it is used daily by many people especially the elderly, without a limitation on the length of the period allowed for continuous use. Harms from long-term use are less clear, particularly in extrahepatic regions.

Aim: This study aimed to investigate whether using paracetamol at a non-observable adverse effect level dose, known not to cause toxic effects, for a long period can induce toxicity in aged male albino rats.

Methods: A daily dose of 500 mg per kg body weight of paracetamol was given to adult male albino rats for 12 weeks. During this period, rats were sacrificed at 4, 6, 8, 10, and 12 weeks to evaluate the toxic changes at several time intervals.

Results: Chemical analysis revealed elevated serum alanine transaminase, aspartate transaminase, alkaline phosphatase, urea, creatinine, and declined level of total protein in N-acetyl-p-aminophenol (APAP)-treated group; it also caused oxidative stress, as shown by decreased glutathione, superoxide dismutase, and elevated malondialdehyde in the liver, kidney, and brain. Histopathological examination demonstrated cytoplasmic vacuolation and sinusoidal congestion with the development of single-cell necrosis in the liver. Renal tubular necrosis, glomerular atrophy, and ischemic neuronal injury, especially in the hippocampus were observed. the deleterious effects of APAP were increased in severity with increasing the period of treatment.

Conclusion: Our results suggest that acetaminophen in a subtoxic dose for a long period could result in mild toxic effects on the liver but more serious lesions in the kidney and brain.

Keywords: Analgesics; Drug side effects; Paracetamol toxicity; Prolonged drug use.

Fig. 1.. The bars represent the means of rat weights, and the lines represent the SD of the mean.

Fig. 2.. Hepatic GSH, SOD, and MDA at different periods of treatment. data indicates the mean ± SD, (n = 5). Means are represented in bars, and SD is represented in T-shaped bars. Horizontal line matching two groups that are significantly different. * p-value p-value p-value <0.001.

Fig. 3.. Renal GSH, SOD, and MDA at different periods of treatment. Data indicates the mean ± SD, (n = 5). Means are represented in bars, and SD is represented in T-shaped bars. Horizontal line matching two groups that are significantly different. * p-value p-value p-value <0.001.

Fig. 4.. GSH, SOD, and MDA in brain tissue at different periods of treatment. Data indicates the mean ± SD, (n = 5). Means are represented in bars, and SD is represented in T-shaped bars. Horizontal line matching two groups that are significantly different. * p-value p-value p-value <0.001.

Fig. 5.. A: The liver of the nontreated group has a normal hepatic lobule with a central vein of normal size. B: The liver of the APAP-treated group after 4 weeks showed congested and dilated sinusoids with blood (arrow). C: liver of the APAP-treated group after 6 weeks showing congestion of sinusoids (arrow) associated with mild cytoplasmic vacuolation (arrowhead). D: Liver of the APAP-treated group after 8 weeks showing hepatic sinusoidal congestion (arrow) and single-cell necrosis associated with acidophilic cytoplasm and pyknotic nucleus (arrowhead). E: liver of the APAP-treated group after 10 weeks showing a dilated central vein surrounded by activated fibroblasts, sinusoidal congestion (arrow), focal necrosis associated with focal hemorrhage, and single-cell necrosis with cytoplasmic eosinophilia and nuclear pyknosis( arrowhead). F: liver of the APAP-treated group after 12 weeks showing a severe degree of perinuclear cytoplasmic vacuolation (arrowhead) with nuclear pyknosis.

Fig. 6.. A: Kidney of the control group showed normal renal tubules (arrow) and a normal glomerulus (arrowhead). B: Kidney of the APAP-treated group after 4 weeks showed capillary congestion (arrow) and the tubular epithelium showed cloudy swelling (arrowhead). C: Kidney of the APAP-treated group after 6 weeks showed severe congestion (arrow) and marked tubular epithelial degeneration with nuclear pyknosis (arrowhead). D: Kidney of the APAP-treated group after 8 weeks showed a severe degree of renal tubular vacuolation with sloughing of tubular epithelium into the lumen of the tubule (arrowheads). E: Kidney of the APAP-treated group after 10 weeks showing tubular epithelial necrosis with nuclear pyknosis and loss (arrowhead) and shrunken glomeruli with widening of Bowman’s space (arrow). F: Kidney of the APAP-treated group after 12 weeks showing severe tubular necrosis of the renal papilla forming eosinophilic structureless masses (arrow) with cytoplasmic vacuolation (arrowhead).

Fig. 7.. A: Brain (cerebral cortex) of the control group shows normal neurons (arrowhead). B: Brain of APAP treated group after 4 weeks showing ischemic neuronal injury (arrowhead). C: Brain of APAP treated group after 6 weeks showing ischemic neuronal injury (arrowhead), and neuronophagia (arrows). D: Brain of APAP treated group after 8 weeks showed severe ischemic neuronal injury (arrowhead), and neuronophagia (arrows). E: Brain of APAP treated group after 10 weeks showing ischemic neuronal injury (arrowhead) neuronophagia (arrow) with satelatosis. F: Brain of APAP treated group after 12 weeks, showing malacia associated with focal gliosis (arrowhead). G: Brain (hippocampus region) of the control group shows normal neurons within the granular layer (arrowhead). H: Brain of APAP treated group after 4 weeks showing ischemic neuronal injury in the hippocampus region (arrowheads). I: Brain of APAP treated group after 6 weeks showing ischemic neuronal injury in the hippocampus region (arrowheads). J: Brain of APAP treated group after 8 weeks showed ischemic neuronal injury in the hippocampus region (arrowhead) also the presence of perivascular oedema. K: Brain of APAP-treated group after 10 weeks showed a large number of ischemic neuronal injuries in the hippocampus region (arrowheads). L: Brain of APAP treated group after 12 weeks showed severe ischemic neuronal injury in the hippocampus region (arrow).

Fig. 8.. Scoring histopathological lesions in the liver (A), kidney (B), and brain (C) data indicates the mean ± SD, (n = 5). Means are represented in bars, and SD is represented in T-shaped bars. Horizontal line matching two groups that are significantly different. * p-value p-value p-value <0.001.