Paracetamol-induced Hepatic Injury Research Articles

A versatile functional food source Lasia spinosa leaf extract modulates the mRNA expression of a set of antioxidant genes and recovers the paracetamol-induced hepatic injury by normalizing the biochemical and histological markers

A versatile functional food source Lasia spinosa leaf extract modulates the mRNA expression of a set of antioxidant genes and recovers the paracetamol-induced hepatic injury by normalizing the biochemical and histological markers

PROTECTIVE EFFECT OF METHANOL EXTRACT OF RUSSELIA EQUISETIFORMIS AGAINST PARACETAMOL-INDUCED HEPATOTOXICITY IN WISTAR RATS

Objectives: Liver diseases are among the health challenges facing many people and health care providers worldwide. In their search for solution to these problems, researchers are increasingly advocating the use of herbal preparations with proven efficacy in protecting against hepatic disorders. They also investigate medicinal plants with the aim of developing new drugs. Russelia equisetiformis is a plant which contains phytoconstituents that were reported to have biological activities, such as anti-inflammatory, antidiabetic, and membrane-stabilizing properties. In this study, the effect of methanol extract of R. equisetiformis (MEREQ) on paracetamol-induced hepatotoxicity was investigated in rats.
 Method: Rats were pretreated orally with graded doses (100 – 400 mg/kg b.w) of MEREQ for 7 days. On the 8th day, hepatotoxicity was induced in the pretreated rats with a single intraperitoneal injection of paracetamol (2 g/kg b.w). Rats were sacrificed on the 15th day; blood samples were taken for biochemical analysis, and the liver was excised for histopathological study. Biochemical parameters analyzed are alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein, albumin, and bilirubin.
 Results: Administration of paracetamol in the rats resulted in significant increase (p<0.05) in the serum levels of AST, ALT, ALP, and bilirubin compared with the control. Treatment with MEREQ significantly reduced (p<0.05) the levels of these parameters in a dose-dependent manner, compared with the untreated rats. No significant changes were observed in the serum levels total protein and albumin. Histopathological examination showed that administration of paracetamol caused distortions in the architecture of the liver, but the degree of degeneration of hepatocytes was reduced in the MEREQ-treated rats.
 Conclusion: From the results obtained in this study, it is concluded that methanol extract of R. equisetiformis has protective effect on paracetamol-induced hepatic injury.
 
 Peer Review History: 
 Received 8 November 2020; Revised 14 Decembe; Accepted 3 January, Available online 15 January 2021
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 Received file: Comments of reviewer(s): 
 Average Peer review marks at initial stage: 6.0/10
 Average Peer review marks at publication stage: 8.0/10
 Reviewer(s) detail:
 Dr. Gehan Fawzy Abdel Raoof Kandeel, Pharmacognosy Department, National Research Centre, Dokki, 12622, Giza, Egypt, gehankandeel9@yahoo.com 
 Prof. Dr. Ali Gamal Ahmed Al-kaf, Sana'a university, Yemen, alialkaf21@gmail.com
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Hepatoprotective effect of Omega-3 PUFAs against acute paracetamol-induced hepatic injury confirmed by FTIR.

Acute paracetamol over dose-induced hepatotoxicity is considered an important medical hazard especially among women. Omega-3 long-chain polyunsaturated fatty acids (Omega-3 PUFAs) daily doses are nowadays recommended for their antioxidant and anti-inflammatory potentials. Fourier transform infrared (FTIR) spectroscopy is considered a reliable method in analyzing cellular alterations and is now efficiently used to diagnose several diseases and the efficacy of drugs even in the early stages. The aim of our study was to evaluate the hepatoprotective effect of Omega-3 PUFAs against paracetamol-induced hepatotoxicity in rats confirmed through measuring protein alterations in hepatocytes by FTIR. Rats were pretreated with Omega-3 PUFAs (50 and 100 mg/kg) for 21 days prior to oral ingestion of paracetamol. FTIR results revealed that Omega-3 PUFAs (50 mg/kg) limited the toxic effects of paracetamol by restoring the hepatic amide I to amide II ratio. In addition; biochemical analyses demonstrated that serum ALT, AST, Cholesterol, LDL-cholesterol and Il-6 levels as well as hepatic TNF-α, MDA, NOx levels were decreased. Besides; serum HDL-cholesterol level and hepatic GSH level were increased. Histopathological examinations of hepatic sections validated the hepatoprotective potential. The overall effect of this dose was comparable to those of the usual recommended hepatoprotective supplement; silymarin. In conclusion; it would be recommended to use Omega-3 PUFAs in low doses on daily bases as a hepatoprotective agent.

Hepatoprotective effect of <i>Helicanthus elastica</i>

<p class="Abstract">Search for medicinal plants to treat liver disorders is an important research topic on herbs. Acute toxicity study is a prerequisite for safety and dose fixation for further pharmacological actions. In the present study, aqueous and 95% ethanolic extract of whole plant of <em>Helicanthus elastica</em> were subjected to acute oral toxicity. The aqueous and ethanolic extract revealed no observable changes in the rats up to the dose level of 2,000 mg /kg body weight. The extracts were then screened for paracetamol-induced hepatic injury at dose levels of 200 and 400 mg/kg body weight (1/10 and 1/5 LD<sub>50 </sub>based on toxicity study). The aqueous extract of whole plant of <em>H. elastica</em> was found to produce significant (p<0.05) reversal of the paracetamol-induced changes in the measured biochemical and histopathological parameters at lower dose of 200 mg/kg which was found to be better than ethanol extract at the same dose level.</p><p class="Abstract"><strong>Video Clip:</strong></p><p class="Abstract"><a href="https://www.youtube.com/v/cO6HI1Kikxs">Acute toxicity study and others:</a> 5 min 38 sec</p><p> </p>

Loss of 5-lipoxygenase activity protects mice against paracetamol-induced liver toxicity.

Paracetamol (acetaminophen) is the most widely used over-the-counter analgesic and overdosing with paracetamol is the leading cause of hospital admission for acute liver failure. 5-Lipoxygenase (5-LO) catalyses arachidonic acid to form LTs, which lead to inflammation and oxidative stress. In this study, we examined whether deletion or pharmacological inhibition of 5-LO could protect mice against paracetamol-induced hepatic toxicity. Both genetic deletion and pharmacological inhibition of 5-LO in C57BL/6J mice were used to study the role of this enzyme in paracetamol induced liver toxicity. Serum and tissue biochemistry, H&E staining, and real-time PCR were used to assess liver toxicity. Deletion or pharmacological inhibition of 5-LO in mice markedly ameliorated paracetamol-induced hepatic injury, as shown by decreased serum alanine transaminase and aspartate aminotransferase levels and hepatic centrilobular necrosis. The hepatoprotective effect of 5-LO inhibition was associated with induction of the antitoxic phase II conjugating enzyme, sulfotransferase2a1, suppression of the pro-toxic phase I CYP3A11 and reduction of the hepatic transporter MRP3. In 5-LO(-/-) mice, levels of GSH were increased, and oxidative stress decreased. In addition, PPAR α, a nuclear receptor that confers resistance to paracetamol toxicity, was activated in 5-LO(-/-) mice. The activity of 5-LO may play a critical role in paracetamol-induced hepatic toxicity by regulating paracetamol metabolism and oxidative stress.

Roles of Lipoxin A4 in Preventing Paracetamol-Induced Acute Hepatic Injury in a Rabbit Model

The objective of this research is to investigate the potential role of lipoxin A4 in preventing paracetamol (PCM)-induced hepatic injury. One hundred male New Zealand white rabbits were randomly divided into control group, PCM group, N-acetylcysteine (NAC) group, lipoxin A4 (LXA4) group, and LXA4 + NAC group. The rabbits were assigned to receive 300 mg/kg weight PCM in 0.9 % saline or equivalent volume of saline via gastric lavage. LXA4 (1.5 μg/kg) and equivalent volume of 2 % ethanol were separately given to the rabbits in LXA4-treated and PCM groups 24 h after PCM administration. Meanwhile, the rabbits in the NAC-treated groups received a loading dose of 140 mg/kg of N-acetylcysteine. The blood samples and liver tissue were collected for biochemical and histological evaluation 36 h after paracetamol administration. The administration of LXA4 24 h after paracetamol poisoning resulted in significant improvement in hepatic injury as represented by decrease of hepatocellular enzyme release and attenuation of hepatocyte apoptosis and necrosis. In LXA4-treated groups, the expression of TNF-α was significantly lower than those in PCM and NAC groups (p < 0.05). In contrast, the level of IL-10 was significantly higher than PCM and NAC groups (p < 0.05). Moreover, the expressions of NF-κB p65 in PCM and NAC groups were significantly increased compared with those of LXA4-treated groups and control group (respectively, p < 0.05 and p < 0.01). LXA4-treated groups also showed significantly higher survival rates. Lipoxin A4 significantly mitigates paracetamol-induced hepatic injury, in which anti-inflammation effect may play an important role, leading to hepatic apoptosis and necrosis.

Hepatoprotective activity of methanol extract of Amaranthus caudatus Linn. against paracetamol-induced hepatic injury in rats

Methanol extract of whole plant of Amaranthus caudatus (MEAC) was screened for hepatoprotective potency against paracetamol (PCM)-induced liver damage in Wistar rats. Rats of five groups were given sodium carboxy methyl cellulose, PCM, MEAC (200 and 400 mg/kg, respectively) plus PCM, and silymarin plus PCM, respectively. Fourteen days after administration, blood samples were collected for biochemical estimation, then animals were sacrificed and liver samples were collected, weighed and subjected for histopathological studies. Liver marker enzymes such as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and serum albumin (ALB), total protein (TP), total bilirubin (TB) and direct bilirubin (DB) levels and the markers for oxidative defense namely malondialdehyde (MDA), reduced glutathione (GSH), total thiols (TT) and catalase (CAT) were measured. MEAC at 200 and 400 mg/kg significantly normalized the PCM-induced biochemical changes compared with PCM-treated group (P<0.01); increased ALT, AST, TB and DB levels and decreased serum ALB were significantly reversed by the MEAC treatment (200 and 400 mg/kg). Treatment with MEAC (200 and 400 mg/kg) significantly prevented the rise of MDA and TP levels (P<0.01), and prevented the reduction of GSH, CAT and TT levels significantly compared with PCM-treated group (P<0.01). Histopathological examination of the liver sections also proved the hepatoprotective activity of MEAC. MEAC shows significant hepatoprotective activity against PCM-induced liver damage in rats. This finding supports the use of the plant in ethnomedicine for the treatment of liver diseases.

Protective effect of tea polyphenols against paracetamol-induced hepatotoxicity in mice is significanly correlated with cytochrome P450 suppression

To investigate the hepatoprotective activity of tea polyphenols (TP) and its relation with cytochrome P450 (CYP450) expression in mice. Hepatic CYP450 and CYPb(5) levels were measured by UV-spectrophotometry in mice 2 d after intraperitoneal TP (25, 50 and 100 mg/kg per day). Then the mice were intragastricly pre-treated with TP (100, 200 and 400 mg/kg per day) for six days before paracetamol (1000 mg/kg) was given. Their acute mortality was compared with that of control mice. The mice were pre-treated with TP (100, 200, and 400 mg/kg per day) for five days before paracetamol (500 mg/kg) was given. Hepatic CYP2E1 and CYP1A2 protein and mRNA expression levels were evaluated by Western blotting, immunohistochemical staining and transcriptase-polymerase chain reaction. The hepatic CYP450 and CYPb(5) levels in mice of TP-treated groups (100, 200 and 400 mg/kg per day) were decreased in a dose-dependent manner compared with those in the negative control mice. TP significantly attenuated the paracetamol-induced hepatic injury and dramatically reduced the mortality of paracetamol-treated mice. Furthermore, TP reduced CYP2E1 and CYP1A2 expression at both protein and mRNA levels in a dose-dependent manner. TP possess potential hepatoprotective properties and can suppress CYP450 expression.

Hepatoprotective activity of Calotropis procera flowers against paracetamol-induced hepatic injury in rats

Hydro-ethanolic extract (70%) of Calotropis procera flowers was prepared and tested for its hepatoprotective effect against paracetamol-induced hepatitis in rats. Alteration in the levels of biochemical markers of hepatic damage like SGPT, SGOT, ALP, bilirubin, cholesterol, HDL and tissue GSH were tested in both treated and untreated groups. Paracetamol (2 g/kg) has enhanced the SGPT, SGOT, ALP, bilirubin and cholesterol levels and reduced the serum levels of HDL and tissue level of GSH. Treatment with hydro-ethanolic extract of C. procera flowers (200 mg/kg and 400 mg/kg) has brought back the altered levels of biochemical markers to the near normal levels in the dose dependent manner.

Lack of Protective Effect of D-003, a Mixture of High-Molecular-Weight Primary Acids from Sugar Cane Wax, on Liver Damage Induced by Galactosamine in Rats

D-003 is a mixture of very-high-molecular-weight aliphatic primary acids purified from sugar cane wax, wherein octacosanoic acid is the most abundant. Experimental and clinical studies have shown that D-003 lowers cholesterol and prevents plasma lipoprotein peroxidation (LP). D-003 has protected against the histological changes characteristic of CCl4- and paracetamol-induced hepatic injury in rats, in which LP plays a pivotal role for explaining the resulting hepatotoxicity. Galactosamine induces hepatotoxicity associated with depressed RNA and protein synthesis, not with LP. The aim of this study was to evaluate whether D-003 could prevent hepatoxicity induced by mechanisms others than increased LP. We investigated the effects on galactosamine hepatotoxicity in rats distributed into five groups: a negative control group, a positive control group, and three groups treated with galactosamine and D-003 (5, 25, and 100 mg/kg). To induce liver damage, galactosamine (800 mg/kg) was injected intraperitoneally 30 minutes after dosing with vehicle or D-003. Twenty-four hours later, rats were sacrificed, and livers were immediately removed for histopathological studies. Livers from positive controls showed the characteristic pattern of galactosamine-induced damage. Galactosamine significantly reduced the percentage of normal hepatocytes, increasing both necrotic or lipid-rich hepatocytes compared with negative controls. D-003, however, did not increase the percentage of normal hepatocytes compared with positive controls, indicating that treatment was not effective for preventing the hepatic injury induced with galactosamine. Likewise, D-003 failed to change the content of necrotic and lipid-rich hepatocytes relative to positive controls. It is concluded that D-003 did not protect against the histological changes of galactosamine-induced hepatotoxicity.

Protection against paracetamol-induced hepatic injury by prazosin pre-treatment in CD-1 mice

A synergistic depletion of glutathione has been suggested to be one critical factor in the hepatic injury in mice induced by non-toxic doses of paracetamol (APAP) when co-administered with α-adrenergic agonists. Prazosin (an α-adrenergic antagonist) could confer hepatoprotection following a toxic APAP dose (530 mg/kg) by increasing glutathione levels and enhancing bioinactivation by glucuronidation and glutathione conjugation. The effect of prazosin pre-treatment on APAP-induced gluthathione depletion and bioinactivation in vivo was assessed. Prazosin (15 mg/kg) pre-treatment provided protection against APAP-induced hepatic injury as evidenced by a significant decrease in serum transaminase (ALT) levels after 5 h ( p < 0.05). Interestingly, prazosin pre-treatment did not prevent the dramatic depletion of glutathione by high dose APAP and it had no effect on the quantity of the glutathione conjugate formed. However, prazosin pre-treatment caused a significant increase in recovery of the administered dose (530 mg/kg) as the glucuronide metabolite ( p < 0.05). UDP-glucuronosyltransferase (UGT) is involved in the bioinactivation of APAP by glucuronidation and we showed that prazosin had no effect on microsomal UGT kinetics. Thus, prazosin had no effect on either APAP-mediated glutathione depletion or the extent of APAP-glutathione conjugate formation and may be affecting other mechanisms to reduce oxidative stress caused by a toxic dose of APAP.