Acetaminophen-induced Liver Damage Research Articles

PROTECTIVE EFFECTS OF VITAMIN C ON ACETAMINOPHEN-INDUCED LIVER AND KIDNEY TOXICITY IN MALE RATS

Acetaminophen (paracetamol) is a widely used over-the-counter analgesic and antipyretic medication known for its efficacy and safety when administered within recommended doses. However, overdose or prolonged use of acetaminophen can lead to severe hepatotoxicity and nephrotoxicity, posing a significant public health concern. This study aims to investigate the protective effects of vitamin C on acetaminophen-induced hepatotoxicity and nephrotoxicity in male Wistar rats. Six rats were randomly assigned to seven groups, with Group 1 designated as the control. Groups 2, 4, and 6 were given daily single oral doses of 100, 200, and 400 mg/kg of acetaminophen, respectively. Meanwhile, Groups 3, 5, and 7 received daily single oral doses of 100, 200, and 400 mg/kg of acetaminophen, followed by intraperitoneal administration of 100 mg/kg of vitamin C daily, for 14 days. Liver function markers (AST, ALT, total bilirubin, and total protein) and renal function indicators (urea and creatinine levels) were assessed, alongside antioxidant status in liver and kidney tissues through antioxidant assays (SOD, CAT, GSH, and MDA). The results demonstrated the protective influence of vitamin C on liver and kidney tissues, as indicated by the modulation of biochemical markers. These findings suggest that vitamin C may play a pivotal role in alleviating acetaminophen-induced liver and kidney damage across different dosage regimens, potentially serving as a therapeutic intervention for preventing or treating drug-induced organ injuries. Further investigations are essential to elucidate the underlying mechanisms and validate the translational potential of vitamin C as a protective agent against acetaminophen toxicity.

Evaluation of the protective effect of losartan in acetaminophen-induced liver and kidney damage in mice

Acetaminophen is widely used among humans as an antipyretic and analgesic. In this study, the protective effect of losartan in hepatotoxicity and nephrotoxicity induced by acetaminophen in mice was investigated owing to its anti-inflammatory and antioxidant effects. An injection of a single dose of 500 mg/kg (i.p.) acetaminophen was administered to induce hepatotoxicity and nephrotoxicity in Groups VI–X. Losartan at doses of 1 mg/kg (Group VII), 3 mg/kg (Group VIII), and 10 mg/kg (Groups III, V, IX, and X) was injected intraperitoneally twice, at 1 and 12 h after the acetaminophen injection. Additionally, a 4 mg/kg dose of GW9662 (peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist) was injected intraperitoneally 30 min before the losartan injections in Groups V and X. At the end of 24 h, the mice were euthanized, and blood, liver, and kidney tissue samples were collected. Levels of AST, ALT, creatinine, and oxidative stress markers including TBARS, SOD, CAT, GPx, TAS, TOS, GSH, and GSSG, along with pro-inflammatory cytokines IL-1β, IL-6, IL-8, IL-10, IL-17, and TNF-α, were measured using ELISA kits. Additionally, a histological evaluation of the tissue samples was performed. Acetaminophen causes increases in the levels of AST, ALT, creatinine, TBARS, TOS, GSSG, IL-1β, IL-6, IL-8, IL-10, IL-17, and TNF-α in serum, liver, and kidney tissue. Meanwhile, it led to a decrease in the levels of SOD, CAT, GPx, TAS, and GSH. Losartan injection reversed oxidative and inflammatory damage induced by acetaminophen. Histopathological changes in liver and kidney tissue were alleviated by losartan. The substance GW9662 increased the protective effect of losartan. In light of all the data obtained from our study, it can be said that losartan has a protective effect on liver and kidney damage induced by acetaminophen due to its antioxidant and anti-inflammatory effects. In terms of the study, losartan was found to be an alternative substance that could protect people from the harmful effects of acetaminophen.

6-Hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline Demonstrates Anti-Inflammatory Properties and Reduces Oxidative Stress in Acetaminophen-Induced Liver Injury in Rats.

We examined the effects of 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline on markers of liver injury, oxidative status, and the extent of inflammatory and apoptotic processes in rats with acetaminophen-induced liver damage. The administration of acetaminophen caused the accumulation of 8-hydroxy-2-deoxyguanosine and 8-isoprostane in the liver and serum, as well as an increase in biochemiluminescence indicators. Oxidative stress resulted in the activation of pro-inflammatory cytokine and NF-κB factor mRNA synthesis and increased levels of immunoglobulin G, along with higher activities of caspase-3, caspase-8, and caspase-9. The administration of acetaminophen also resulted in the development of oxidative stress, leading to a decrease in the level of reduced glutathione and an imbalance in the function of antioxidant enzymes. This study discovered that 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline reduced oxidative stress by its antioxidant activity, hence reducing the level of pro-inflammatory cytokine and NF-κB mRNA, as well as decreasing the concentration of immunoglobulin G. These changes resulted in a reduction in the activity of caspase-8 and caspase-9, which are involved in the activation of ligand-induced and mitochondrial pathways of apoptosis and inhibited the effector caspase-3. In addition, 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline promoted the normalization of antioxidant system function in animals treated with acetaminophen. As a result, the compound being tested alleviated inflammation and apoptosis by decreasing oxidative stress, which led to improved liver marker indices and ameliorated histopathological alterations.

Evaluation of hepatoprotective activity of the aqueous extract of Vitis vinifera against acetaminophen-induced liver damage in rats

In this study we evaluated the hepatotoxicity activity of Vitis vinifera in acetaminophen induced liver damage in rats. Five (5) Groups of rats were used for the study, Group 1 received normal saline (1ml /kg, p.o), Group II received acetaminophen (300mg/kg, i.p), Group III received (300mg/kg, i.p) acetaminophen and (150mg/kg, o.p) Vitis vinifera juice, Group IV received ( 600mg/kg, i.p) acetaminophen and (300mg/kg, o.p) Vitis vinifera juice while Group V received ( 600mg/kg, i.p) acetaminophen and Silymarin (25mg/kg, o.p) simultaneously once daily for four (4) days. Acute toxicity study and histopathological analysis were carried out. The LD 50 was found to greater than 4000mg/kg body weight. The aqueous extract of Vitis vinifera significantly (P< 0.05*) reduced the hepatic enzymes from aspartase transaminase ( AST ) (415 ± 0.2* to 94.5 ± 0.8*) alanine transaminase (ALT) (132 ± 2.2 * to 60.5 ± 0.2*) and alkaline phosphase ALP (118± 0.6 * to 87.5 ± 2.1*) while there were no significant changes in the total bilirubin (TB) and direct bilirubin levels comparable to the reference drug. These findings confirm the histopathology study which indicated no adverse effects on the liver. The aqueous extract of the Vitis vinifera possesses hepatoprotective activity against acetaminophen induced liver damage, therefore further studies should be carried out to determine the exact mechanism of action as well as phytochemicals responsible for these activities.

Evaluation the anti-inflammatory effect of Omega 369 against acetaminophen-induced hepatotoxicity in mice

Background: Acetaminophen (N-acetyl-para-aminophenol, or APAP) poisoning, whether intentional or accidental, is a major general health problem, with its toxicity prevalence significantly increasing in many countries. Currently, acetaminophen is considered one of the main causes of acute liver failure globally.Aim: The aim of this study was to evaluate the possible hepatoprotective effect of Omega-3,6,9 against acetaminophen-induced hepatotoxicity in albino male mice.Methods: Thirty-five albino male mice were randomly divided into five groups: Group 1 (the negative control) received liquid paraffin orally at a dose of 10 ml/kg for ten days, followed by a single intraperitoneal injection (IP) of 10 ml/kg normal saline on the eleventh day of the test. Group 2 (positive control) received liquid paraffin. Group 3 was treated with Omega-3,6,9 (50 mg/kg/80 mL). Group 4 was treated with Omega-3,6,9 (100 mg/kg/35 mL). Group 5 was treated with N-acetylcysteine (100 mg/kg/10 ml). The mice were treated with Omega-3,6,9, N-acetylcysteine, and liquid paraffin once daily by oral gavage for ten days.Result: TNF-α, IL-10, ALT, and AST levels in the positive control group were significantly higher than those in the negative control group. TNF-α, IL-10, ALT, and AST levels in mice given Omega-3,6,9 (50 mg/kg), Omega-3,6,9 (100 mg/kg), and N-acetylcysteine (100 mg/kg) orally prior to acetaminophen injection were significantly decreased compared to those in the positive control group.Conclusion: Oral intake of Omega-3,6,9 may reduce the risk of acetaminophen-induced liver damage.

Hepatoprotective role of tecomella undulata bark extract in comparison with n- acetylcysteine on acetaminophen induced hepatotoxicity in albino rats.

Objective: To assess hepatoprotective effect of Tecomella Undulata bark extract on acetaminophen induced hepatotoxicity in albino rats as compared to N-Acetylcysteine. Study Design: Experimental Comparative Study. Setting: Bahria University Medical & Dental College Karachi in collaboration with Basic Medical Sciences Institute Karachi. Period: March 2020 till August 2020. Material & Method: Study included 56 Albino rats divided in four groups with 14 animals in each group. Group A was control, Group B was induced hepatotoxicity by giving Acetaminophen 500 mg as a single dose, Group C was given N–Acetylcysteine 140mg/kg intraperitoneally for 6 days and Group D was given Tecomella bark extract 200mg/kg for 15 days after acetaminophen induced liver damage. Their blood samples were collected and sent for hepatic enzyme levels. Statistical analysis was done using SPSS version 23. One way ANOVA was applied. For multiple comparison post hoc tukey’s test was used. P-value <0.05 was considered significant. Result: The mean Serum AST, ALT and ALP levels were increased in Group-B, however, Group-D showed significant reduction in hepatic enzyme levels as compared to Group-C. Tecomella bark extract showed hepatoprotective effect by reducing hepatic enzyme levels in acetaminophen induced hepatic damage in albino rats. Conclusion: Thus Tecomella plant extract could act as an alternative antidote to N-acetylcysteine in acetaminophen induced hepatic damage in albino rats.

Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.

Histopathological effects with marwar teak (tecomella undulata) bark extract and N-acetylcysteine on acetaminophen induced hepatotoxicity in albino rats.

Objective: The study aims to determine histopathological effects associated with Marwar Teak Tecomella Undulata bark extract and N-Acetylcysteine on Acetaminophen induced liver damage in rats. Study Design: Experimental Comparative Study. Setting: Bahria University Medical and Dental College Karachi in Collaboration with Basic Medical Sciences Institute (BMSI) Karachi. Period: March 2020 till August 2020. Material & Methods: Study included 56 healthy albino rats which were randomly divided into four groups. Each group comprised of 14 experimental animals which included (Group-1) Control Group, (Group-2) hepatotoxicity induced rats, which were given Acetaminophen 500 mg as a single dose orally, (Group 3) which was induced hepatotoxicity by Acetaminophen 500mg orally as a single dose, then they were given N-Acetylcysteine standard drug at dosage of 140mg/ kg intraperitonealy for 6 days and (Group 4), which was induced hepatotoxicity by Acetaminophen 500 mg orally as a single dose, then they were given Tecomella bark extract at the dose of 200 mg/kg orally for 15 days. Experimental animals were dissected. Liver samples were sectioned (3-5µ) thickness and were stained with H&E. Histopathological findings were noted. SPSS version 23 was used for statistical analysis. P-value <0.05 was considered significant. Result: Deranged liver architecture with presence of moderate inflammatory cells were observed in Acetaminophen induced hepatotoxic rats (Group-2). However, there was presence of moderate inflammatory cells with normal liver architecture in rats treated with standard drug (Group–3). There was improvement in liver histology in Tecomella bark extract treated group (p-<0.05) Group-4. Conclusion: The Tecomella Bark extract improved histoarchitecture on acetaminophen induced hepatotoxicity in albino rats in comparison with N-Acetylcysteine.

The hepatoprotective effect of Marchantia paleacea bertol. extract against acetaminophen-induced liver damage in rat: biochemical and histological evidence

The hepatoprotective effect of Marchantia paleacea bertol. extract against acetaminophen-induced liver damage in rat: biochemical and histological evidence

The difference of chows affects mouse physiological conditions.

Acetaminophen-induced liver injury in mice is a model system of human acetaminophen overdose and oxidative stress in vivo. The system is technically established, and we usually obtain severe liver damage in the treated mice; however, it is possible that the degree of liver damage is affected by the type of chow fed to mice. Thus, in this experiment, we investigated the effect of different chows on mice by comparing acetaminophen-induced liver damage, liver antioxidant level, and serum amino-acid concentrations. The results showed that differences in chows, even standard ones, affected mouse physiological conditions, with the response to oxidative stress greatly affected.

CD5L deficiency attenuate acetaminophen-induced liver damage in mice via regulation of JNK and ERK signaling pathway

CD5 molecule like (CD5L), a member of the scavenger receptor cysteine-rich domain superfamily, plays a critical role in immune homeostasis and inflammatory disease. Acetaminophen (APAP) is a safe and effective antipyretic analgesic. However, overdose may cause liver damage or even liver failure. APAP hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response, in which the role of CD5L remains to be investigated. In this study, we found that the expression of CD5L was increased in the livers of mice after APAP overdose. Furthermore, CD5L deficiency reduced the increase of alanine transaminase (ALT) level, histopathologic lesion area, c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) phosphorylation level, Transferase-Mediated dUTP Nick End-Labeling positive (TUNEL+) cells proportion, vascular endothelial cell permeability and release of inflammatory cytokines induced by excess APAP. Therefore, our findings reveal that CD5L may be a potential therapeutic target for prevention and treatment of APAP-induced liver injury.

The ameliorative effect of the solvent extracts of Ocimum basilicum against acetaminophen-induced liver damage in albino rats

This study was designed to evaluate the protective activities of 4 different Ocimum basilicum L whole plant extracts against acute acetaminophen-induced liver damage in albino rats. A total of 42 rats were divided into 7 groups comprising the control (acetaminophen, water, and silymarin treated) groups and OB-treated (chloroform, diethylether, ethylacetate, and methanol extract) groups. Each treatment group was made up of 6 rats, with 3 replicates of 2 rats each. At the end of the treatment period, blood samples were collected to investigate the activities of liver enzymes, and liver tissue was harvested for histological analysis. Rats pre-treated with OB extracts showed decreased (p<0.05) ALT, AST, and ALP activities when compared with the silymarin-treated and positive control groups. Serum urea decreased (p<0.05) in OB-treated groups compared to the control groups and least (p<0.05) activity was seen in rats pre-treated with diethyl ether and methanol extracts. Rats pre-treated with OB extract (except diethyl ether extract) showed decreased (p<0.05) creatinine activity in comparison with the positive control group. The decreased value of serum total bilirubin and D bilirubin in rats pretreated with OB methanol extract was comparable to those of negative control. Histopathological examination revealed hepatic tissue necrosis in the acetaminophen-induced rats and varying degrees of injury and amelioration in other groups. The results from of all the solvent extracts of OB whole plant suggest significant hepatoprotective and antioxidant activities with the methanolic extract having higher hepatoprotective activity than the standard, Silymarin, and other solvent extracts.

Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

Cullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2–3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.

Echinacoside alleviates acetaminophen-induced liver injury by attenuating oxidative stress and inflammatory cytokines in mice.

This study evaluates the protective effect of Echinacoside on acute liver toxicity induced by acetaminophen in mice and the mechanism behind it. Echinacoside and N-Acetyl Cysteine were intragastrically administrated for 7 days, and acetaminophen was intraperitoneally injected into mice 1 h after the last treatment on day 7. At the end of the experimental period, histological examination, parameters for the level of oxidative damage, hepatic malondialdehyde, serum pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1β), UDP-glucuronosyltransferases, and sulfotransferases changes were examined using enzyme-linked immunosorbent assay and standard biochemical procedures. The expression of cytochrome P450 2E1 protein was assessed by western blot, followed by in silico molecular docking. Acetaminophen treatment obviously increased the levels of ALT and AST, changed hepatic histopathology, promoted oxidative stress, decreased antioxidant enzyme activities, and elevated the pro-inflammatory cytokines. Echinacoside significantly attenuated Acetaminophen-induced liver damage in a dose-dependent manner, with the most effective dose at 100 mg/kg. The pretreatments of Echinacoside in different concentrations altered the Acetaminophen-induced hepatotoxicity levels by decreasing the level of liver enzymes, reducing the liver necrosis with vacuolization, decreasing the hepatic malondialdehyde formation, increasing hepatic antioxidants activities, suppressing the pro-inflammatory cytokines (Tumor Necrosis Factor, Interleukin-6 and Interleukin-1beta), inhibiting Nitric Oxide production, enhancing sulfotransferases and UDP-glucuronosyltransferases activities. Notably, the expression of cytochrome P450 2E1 was inhibited by Echinacoside in a dose-dependent manner and the binding energy was -214.3 MeV. Echinacoside showed a significant protective effect against Acetaminophen-induced hepatotoxicity through the inhibition of oxidative stress, the expression of pro-inflammatory cytokines and cytochrome P450 2E1 protein expression.

Comparative Effect of Ginger (Zingiber officinale) Supplement on Hepato-renal Damages Induced by Acetaminophen Toxicity in Wistar Rats

Background: Acetaminophen toxicity is one of the widespread causes of both planned and unplanned health related issues in the world today. It is a familiar cause of liver and kidney damage particularly in adolescents and children.
 Aims: With the growing focus in the mitigating and therapeutic roles of herbal drugs in toxicity studies, it is perceptible to investigate the comparative, prophylactic and curative effect of the ginger supplement on acetaminophen-induced liver and kidney damage using wistar rats as model. Methodology:
 Study Design: Twenty (20) adult male wistar rats weighing185 g-220 g was obtained from animal house of the department of Pharmacology University of Port Harcourt were divided into four groups having five rats each. 
 Methodology: Twenty adult wistar rats were divided into four (4) groups of five animals each and treated orally as follows: Group A (normal control) received distilled water (7days), group B received 1000mg/kg acetaminophen (APAP) (2 days). Group C Ginger (GINE+APAP) received ginger supplements 500mg/kg respectively one hour before administration of APAP for 7 days, whereas group D received APAP (2 days) followed by 500mg/kg Ginger for 5 days (APAP+GINE). At the end of the experiment, animals from different groups were anaesthesized, blood samples collected, liver and kidney tissues dissected and subjected to different biochemical, antioxidants, and histopathological test.
 Statistical: Analysis was done using One Way Anova and Tukey’s Post-hoc Test. 
 Results: APAP caused significant (P<0.05) decrease in creatinine with significant (P<0.01) increase and decrease in liver enzymes and hepatic catalase levels respectively in relation to normal control. Treatment of rats with the ginger supplements attenuated the elevated liver and kidney biochemistry, histopathological alterations by APAP treatment.
 Conclusively: The extracts demonstrated therapeutic ability and the herbal drugs may be more effective when use prophylactically than curatively. Further research work is needed to validate the finding.

Kaempferol suppresses acetaminophen-induced liver damage by upregulation/activation of SIRT1

Context Kaempferol, a flavonoid glycoside, has many hepatoprotective effects in several animals due to its antioxidant potential. Objective This study evaluated the hepatoprotective effect of kaempferol against acetaminophen (APAP)-induced liver damage and examined whether the protection involved modulation of silent information regulator 1 (SIRT1) signalling. Materials and methods Adult male Wistar rats were classified into four groups (n = 8) and treated as follows: control + normal saline (vehicle), control + kaempferol (250 mg/kg), APAP (800 mg/kg, a single dose) and APAP + kaempferol. Kaempferol was administered for the first seven days followed by administration of APAP. The study was ended 24 h after APAP administration. Results At the histological level, kaempferol reduced liver damage in APAP-treated rats. It also reduced the hepatic levels of TNF-α (66.3%), IL-6 (38.6%) and protein levels of caspase-3 (88.2%), and attenuated the increase in circulatory serum levels of ALT (47.6%), AST (55.8%) and γ-GT (35.2%) in APAP-treated rats. In both the controls and APAP-treated rats, kaempferol significantly increased the hepatic levels of glutathione (GSH) and superoxide dismutase, suppressed MDA and reactive oxygen species (ROS) levels, increased protein levels of Bcl-2 and downregulated protein levels of Bax and cleaved Bax. Concomitantly, it reduced the expression of CYP2E1, and the activity and protein levels of SIRT1. Consequently, it decreased the acetylation of all SIRT1 targets including PARP1, p53, NF-κB, FOXO-1 and p53 that mediate antioxidant, anti-inflammatory and anti-apoptotic effects. Discussion and conclusions This study encourages the use of kaempferol in further clinical trials to treat APAP-induced hepatotoxicity.

Histopathological effect of aqueous bitter leaf extract (Vernonia amygdalina) on acetaminophen-induced liver damage in albino rat (Rattus norvegicus)

Liver diseases are a worldwide problem. Medicinal plants are being increasingly utilized to treat a wide variety of diseases, liver disorder inclusive. The effect of aqueous leaf extracts of Vernonia amygdalina on acetaminophen-induced liver damage via the assessment of the histopathological examination was examined. Five groups of albino rats were used (n = 5). Animals in group 1 were fed normal laboratory pellet and water ad libitum (Control); those in group 2 received 3000mg/kg of acetaminophen alone. Groups 3, 4 and 5 received 3000mg/kg of acetaminophen and in addition 50mg/kg Vernonia amygdalina leaf extract. 100mg/kg Vernonia amygdalina leaf extract and 200mg/kg Silymarin, respectively for 14 days. Twenty-four hours after the last administration, the animals were sacrificed. The organs (liver) was excised and used for the histopathological examination. Histological examinations of the liver showed acetaminophen-induced hepatotoxicity. Histology of the liver revealed altered cellular architecture (poor architecture, moderate to severe congestion of the portal vein as well as severe peri portal infiltration of inflammatory cells, the liver parenchyma also showed area with destroyed liver plates with severe hemorrhage and necrosis. The morphology of the hepatocytes showed some degenerated liver cells, the liver parenchyma also showed focal area of moderate aggregate of inflammatory cells) following administration of acetaminophen (Group 2). Normal histological features were restored after treatment with aqueous leaf extract of Vernonia amygdalina. The study has demonstrated that aqueous leaf extract of Vernonia amygdalina ameliorate liver of rats against acetaminophen-induced toxicity and modulates the adverse effects of acetaminophen on the liver

Dehydroepiandrosterone protects against acetaminophen-induced liver damage in rats by upregulation of Bcl-2 and activation of sirt signalling.

The study examined the protective effect of exogenous administration of dehydroepiandrosterone (DHEA) against acetaminophen (APAP) -induced liver damage in rats and tested the underlying mechanism(s). Male rats were divided into 5 groups as control, control + DHEA, APAP, APAP + DHEA, and APAP + DHEA + EX-527 (SIRT1 inhibitor). Treatments were conducted for 10 days and then followed by intragastric administration of a single dose of APAP. DHEA not only reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) but also preserved the liver structures. Besides, DHEA reduced hepatic levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), Bax, cleaved caspase-3. In the livers of both the control and APAP-treated rats, DHEA suppressed the generation of reactive oxygen species (ROS) and malondialdehyde (MDA), increased levels of glutathione (GSH), MnSOD (SOD2), and Bcl-2 levels, lowered Bax/Bcl-2 ratio, enhanced the activity of nuclear factor erythroid-derived 2-like 2 (Nrf2), and inhibited nuclear factor kappaB (NF-κB) p65. All these effects coincided with a significant increase in the levels and activity of SIRT1 and a reduction in the acetylation of Nrf2, p53, forkhead box class O transcription factor 1 (FOXO1), and NF-κB p65. Except for Bcl-2, treating the rats with EX-527 abolished the beneficial effects of DHEA on all these markers. In conclusion, DHEA prevents APAP-induced liver damage by concomitant upregulation of Bcl-2 and SIRT1-dependent effect.

Protective potentials of ethyl acetate-ethanolic fraction of Carica papaya leaves against acetaminophen-induced liver damage in rats

The liver is an important organ performing vital roles that become affected when damaged. The protective potential of ethyl acetate-ethanolic fraction of Carica papaya leaves on acetaminophen-induced liver damage in female albino rats was investigated. Forty female rats were completely randomized into eight groups (A-H) of five rats each. Group A (control), received 1 ml of distilled water, group B (untreated) received 250 mgkg-1 bw of acetaminophen, group C received silymarin (50 mgkg-1 bw) followed by actaminophen (250 mgkg-1 bw), groups D-G received 100, 200, 400 and 600 mgkg-1 bw of ethyl acetate-ethanolic fraction of Carica papaya leaves respectively; followed by acetaminophen administration (250 mgkg-1 bw), while group H (toxicity control) received 600 mgkg-1 bw extract fraction daily. Ethyl acetate-ethanolic fraction of Carica papaya leaves significantly (p<0.05) decreased the activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase and bilirubin concentration and increased the concentrations of total protein and albumin in acetaminophen-induced liver damaged rats when compared with the untreated group. Prevention of liver damage was observed in the groups pre-administered 400 and 600 mgkg-1 bw of the extract fraction as well as the silymarin group. Activities of superoxide dismutase and catalase and the concentration of glutathione were significantly (p<0.05) increased while the concentration of malondialdehyde was significantly (p<0.05) decreased in rats pre-administered with silymarin or the extract fraction when compared with the acetaminophen-induced rats. Ethyl acetate-ethanolic fraction of Carica papaya leaves prevented acetaminophen-induced rat liver damage probably mainly due to the antioxidant constituents of the fraction.

Drug Induced Hepatotoxicity – An Ongoing Challenge

Drug induced liver injury is one of the main factor of liver failure and acute liver damage world wide with high incidence in western countries. Liver injury can be intrinsic (dose dependant) or idiosyncratic (dose independent). However idiosyncratic type is considered to be mainly responsible for drug induced liver damage. Binding of reactive metabolites of drugs to tissue proteins and oxidative stress is the possible cellular mechanism involved in this process. Moreover, some antibiotics, anti-epileptics, nonsteroidal anti-inflammatory drugs etc are more likely to induce liver damage in high risks groups that includes females, elderly and obese people. HLA halotype and variation in protein expression also plays an important role in this context. Various studies are available regarding clinical features, histopathological features, diagnosis and management related to antibiotics and acetaminophen induced liver damage. N acetylcysteine is commonly available antidote for drug induced hepatic damage. Role of other pharmacological agents as an antidote requires further studies. However, liver transplantation should be considered with drug induced lethal liver failure