Acetaminophen-induced Liver Toxicity Research Articles

Hepatoprotective effect of amifostine and WR-1065 on acetaminophen-induced liver toxicity on Wistar rats.

The most important problem with acetaminophen is its hepatotoxicity. N-acetylcysteine (NAC) is used to treat the hepatotoxicity of acetaminophen. Due to the structural similarities of this compound with amifostine, we decided to test the effect of this substance and its metabolite, WR-1065, on the hepatotoxicity of acetaminophen. The single-dose method contained 1. Control; 2. Acetaminophen (1 g/kg, gavage); 3-5. Acetaminophen + amifostine (100, 200, 400 mg/kg, i.p.); 6-8. Acetaminophen + WR-1065 (50, 100, 200 mg/kg, i.p.); and 9. Acetaminophen + NAC (100, 200 mg/kg, i.p.). The multiple-dose method included the same groups: amifostine (50, 100, 200 mg/kg), WR-1065 (25, 50, 100 mg/kg), and NAC (100 mg/kg). Then, animals were sacrificed, and blood samples were collected for measuring ALT, AST, ALP, and T-Bil, liver tissue for histopathological examination, MDA, and GSH amounts. Acetaminophen increased the levels of MDA, T-Bil, ALT, AST, and ALP, decreased GSH levels, and augmented necrosis, neutrophils, lymphocytes, and macrophages in the port space in single-dose and multiple-dose studies. Amifostine and WR-1065 significantly reduced the levels of MDA, T-Bil, ALT, AST, ALP, increased GSH content, and ameliorated histopathological alterations in a single-dose and multiple-dose method compared to the acetaminophen group. Moreover, NAC caused a significant decrease in the levels of MDA, T-Bil, ALT, AST, and ALP, and reduced GSH amounts in single-dose and multiple-dose studies. Amifostine and WR-1065 as antioxidant and hepatoprotective compounds are effective in reducing acetaminophen-induced hepatotoxicity with a similar effect to NAC and can be administered as an adjunct in the treatment of acetaminophen overdose.

Antioxidant and hepatoprotective effects of hypericum sampsonii

Hypericum sampsonii or Sampson’s St John’s Wort is a species of flowering plant in the Hypericaceae family. Our previous study revealed the diverse and bioactive chemical constituents of the plant. This study investigates the antioxidant activity and potential hepatoprotective of Hypericum sampsonii extract (BLD1 extract) in vitro and in vivo. The in vitro experiment was carried out with DPPH (1, 1-diphenyl-2-picrylhydrazyl) radical scavenging assay to assess the antioxidant properties of BLD1 extract. In the in vivo experiment, the hepatoprotective activity of BLD1 extract was evaluated on an acetaminophen-induced hepatotoxicity mouse model. The in vitro assay demonstrated that the extract exhibited antioxidant activity in a dose-dependent manner. In the in vivo experiments, BLD1 extract at both doses (3.6 g/kg b.w day and 10.8 g/kg b.w day) reflected the decrease in serum ALT, AST and MDA level. Hepatic histology was also investigated post-mortem to assess the degree of liver injury. The overall findings of this study demonstrate the potential hepatoprotective effect of Hypericum sampsonii in acetaminophen-induced oxidative stress and liver toxicity in mice. This study has established the efficacy of Hypericum sampsonii, which should warrant further clinical trials and applications.

Investigating the Preventive and Therapeutic Role of Costus afer in Acetaminophen Induced Liver Toxicity

The objective of this study was to determine the prophylatic and therapeutic role of Costus afer in acetaminophen poisoning in rats. The rats were equally divided into two groups; pre-treatment group and post-treatment group with each group have five sub-groups (negative control (NC), positive control (PC), A, B and C) of 5 rats each. NC was without any treatment; PC was treated with 800mg/kg of acetaminophen; A was treated with 200mg/kg of Costus afer; B was treated with 400mg/kg of Costus afer; C was treated with 800mg/kg of Costus afer. In the pre-treatment group, the PC was induced with acetaminophen 28 days after administration of distilled water, and “A”, “B” and “C” were induced with acetaminophen 28 days after Costus afer treatment while in the post-treatment group, the PC was induced with acetaminophen before commencing on 28 days administration of distilled water, and “A”, “B” and “C” were induced with acetaminophen before commencing on 28 days Costus afer treatment. After the treatment period, the rats were sacrificed and sample and liver organ were collected for laboratory analysis for liver enzymes and histological studies. The results showed that there was no significant change (p>0.05) in liver enzymes in the A, B, C subgroups of the pre-treatment group after acetaminophen induction. In the post-treatment group, there was a significant decrease in the liver enzymes in A, B and C subgroups after Costus afer treatment. This study has proven that Costus afer has the potential to not only prevent acetaminophen liver toxicity but to also treat hepatotoxicity inflicted by acetaminophen in rats.

Mitigation of acetaminophen-induced liver toxicity by the novel phosphatidylinositol 3-kinase inhibitor alpelisib.

The sterile inflammatory response mediated by Toll-like receptors (TLRs) 4 and 9 is implicated in the massive hepatic damage caused by acetaminophen (APAP)-overdose. There is a crosstalk between TLR-dependent signaling with other intracellular kinases like phosphatidylinositol 3-kinases (PI3Ks). Nevertheless, the detailed role of PI3Kα is still unknown in hepatic sterile inflammation. Accordingly, the effect of the novel PI3Kα inhibitor alpelisib was investigated in the setting of APAP-driven sterile inflammation in the liver. This was examined by pretreating mice with alpelisib (5 and 10mg/kg, oral) 2h before APAP (500mg/kg, i.p.)-intoxication. The results indicated that alpelisib dose-dependently lowered APAP-induced escalation in serum liver function biomarkers and hepatic necroinflammation score. Alpelisib also attenuated APAP-induced rise in cleaved caspase 3 and proliferating cell nuclear antigen (PCNA) in the liver hepatocytes, as indices for apoptosis and proliferation. Mechanistically, inhibition of PI3Kα by alpelisib limited APAP-induced overproduction of the pro-inflammatory tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6 in the blood circulation via switching off the activation of several signal transduction proteins, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), signal transducer and activator of transcription-3 (Stat-3), glycogen Synthase Kinase (GSK)-3β and nuclear factor (NF)-κB. Alpelisib also impaired APAP-instigated immune cell infiltration in the liver via reducing systemic granulocyte/macrophage-colony stimulating factor (GM-CSF) release and reversed APAP-induced abnormalities in the systemic and hepatic levels of the anti-inflammatory IL-10 and IL-22. In conclusion, selective modulation of the PI3Kα activity by alpelisib can hinder the inflammatory response and infiltration of immune cells occurring by APAP-hepatotoxicity.

Alleviation of acetaminophen-induced liver failure using silibinin nanoliposomes: An in vivo study

BackgroundAcetaminophen (Act) overdose is a known inducer of liver failure in both children and adults. Cell annihilation ensues following acetaminophen overdose and its toxic metabolites by depleting cellular GSH storage and increasing ROS levels. Silymarin extract and its major compound silibinin (SLB) possess robust antioxidant properties by inducing ROS elimination; however, low bioavailability and rapid metabolism limit their applications. Herein, we aimed at using SLB liposomes to combat acetaminophen-induced acute liver toxicity. MethodsWe have developed a SLB-lipid complex to improve SLB loading efficiency within nanoliposome by using the lipid film method. Liposomes were characterized by using DLS and TEM analysis, and the release pattern, and toxicity profile on the normal cells as well as histopathological and serum analysis were investigated to reveal relevant enzyme activities in an animal model. ResultsData demonstrated that negatively-charged SLB liposomes of 115 nm had homogeneous spherical morphology, and entrapped a considerable quantity of SLB of almost 40%. Liposomes shows a favorable release pattern and were not toxic against NIH3T3 mouse fibroblast cells. The animal study revealed that treatment of mice with SLB nanoliposomes could significantly preserve liver function as revealed by the reduced levels of ALT and AST hepatic enzymes as well as ALP in the serum. Our data indicated that intraperitoneal administration of SLB Lip could significantly reduce ALT enzyme levels (p < 0.05) compared to N-acetylcysteine, while i.v administration resulted in no significant difference compared to control animals with no treatment. ConclusionThe results of this study support the significant hepatoprotective effect of SLB nanoliposomes against acetaminophen-induced toxicity depending on the route of administration.

Geometric Isomer of Guanabenz Confers Hepatoprotection to a Murine Model of Acetaminophen Toxicity.

Overdose of acetaminophen, a widely used antipyretic and analgesic drug, is one of the leading causes of drug-induced acute liver injury in the United States and worldwide. Phase-I metabolism of acetaminophen generates the toxic N-acetyl-p-benzoquinone imine (NAPQI) intermediate. Reactions of NAPQI with a wide range of biomolecules cause increased oxidative stress, endoplasmic reticulum (ER) stress, inflammation, and mitochondrial dysfunction, some of the cellular events contributing toward liver toxicity. Previously, we evaluated the potential of an FDA-approved, ER stress-modulating antihypertensive drug, Wytensin (trans-guanabenz, E-GA), as an antidote for acetaminophen hepatotoxicity. E-GA prevented elevation of the liver enzyme alanine aminotransferase (ALT), even when administered up to 6 h after acetaminophen overdose, and exhibited synergistic analgesic interactions. However, the commercially available guanabenz exists solely as a trans-isomer and suffers from sedative side effects resulting from the inhibition of central α2A-adrenergic receptors in locus coeruleus. Here, we studied the utility of the relatively unexplored cis-isomer of guanabenz as a treatment option for acetaminophen-induced liver toxicity. cis(Z)-Guanabenz acetate (Z-GA) lacks interaction with α2A-adrenoreceptors and is thus devoid of sedative, blood-pressure-lowering side effects of E-GA. Treatment of mice with Z-GA (10 mg/kg) before acetaminophen overdose and up to 6 h post APAP administration prevented liver injury and suppressed the elevation of serum ALT levels. Mechanistically, hepatoprotective effects of both isomers are similar and partly attributed to attenuation of the ER stress and oxidative stress in the liver. The results of this study suggest that Z-GA may be a safer, effective antidote for the clinical management of acute liver injury resulting from acetaminophen overdose. It also raises a tantalizing possibility of a prophylactic combination of the geometric isomer of the approved drug guanabenz with acetaminophen in a clinical setting.

Hepatoprotective Role of Virgin Coconut Oil and Neem Extract in Acetaminophen Induced Liver Toxicity

Aim: To study the comparative hepatoprotective effect of Virgin Coconut Oil (VCO) and Neem (Azadirachta indica) leaf extract in acetaminophen (Paracetamol) induced liver toxicity. Methods: About 60 mixed population of rats (male/female) of Wistar and Sprague-Dawley species were randomly selected for the proposed study and are segregated into four equal groups. Every group contains 15 animal subjects. Group A was the control group given normal diet. In Group B, the rats were treated with a single dose of 2gm / kg body weight paracetamol, orally. Simultaneously, Group C were given an oral Neem extract of 500mg/kg body weight for 2 weeks days in combination with single dose of Paracetamol, while Group D were provided with 6.7ml/Kg/body weight Virgin Coconut Oil (VCO) for 15 days. Data was analyzed using SPSS Version 20.0 with level of significance being kept at p-value ≤0.05. Results: The mean values of ALT were 23.1, 100.5, 29.85, and 31.09 U/L in Group A, B, C, and D respectively. While, the mean values of AST were 25.6 U/L (Group A), 41 U/L (Group B), 19.3 U/L (Group C), and 15.2 U/L (Group D). The ALP showed maximum response indicated by the mean values of 221 U/L, 444 U/L, 241 U/L, and 243 U/L in Group A, B, C, and D respectively. Group B suggested the paracetamol induced liver toxicity indicated by the increase in hepatic DMEs right after the acetaminophen induction. Conclusion: Azadirachta Indica and Virgin Coconut Oil displayed hepatoprotective effects on the Wistar and Sprague-Dawley rats that were subjected to Paracetamol. Keywords: hepatic, Drug Metabolizing enzymes, Acetaminophen, Virgin coconut oil, Neem extract, Paracetamol, Wistar

Antioxidative Role of Azadirachta Indica Vit. E in Restoration of Histopathological changes in Acetaminophen induced liver

Aim: To study the comparative effect of Acetaminophen induced liver toxicity with aqueous extract of Azadirachta Indica (Neem) and vitamin E on the basis of liver Histopathology. Methods: Sixty Wistar Rats of both sexes were split into four groups. Each group contained 15 animals. The control group was group A, Group B was treated orally with single dose of Paracetamol 2 mg / kg by weight, Group C was administrated orally with aqueous Neem extract 500 mg/kg +2 mg/Kg by weight oral Paracetamol, and Group D was given orally paracetamol+Neem extract+Vitamin E with 100mg/Kg/body weight for 15 days. Rats from all groups were decapitated, the liver was sliced, and liver tissues were taken for histological examination. Tissue samples were fixed in 10% formaldehyde, embedding in paraffin followed by Hematoxylin and Eosin dye (H&amp;E) and observed under 400x magnification with a digital microscope. Results: On Histopathological examination of the rat`s liver in we found that the control group had a normal appearance, colour, and uniform surface without any necrosis. Group B showed severe necrosis and haemorrhagic patches. In comparison, Group C revealed normal appearance, colour, and smooth surface with no necrotic alterations. Livers from the group D looked virtually normal in terms of colour, undersurfaces, and organ weight. However, hepatoprotective effects were observed in the Group C and D. Therefore, we can conclude that Azadirachta indica and Vitamin E could serve as a good medication for defence against liver injury. Conclusion: Our findings showed thatextract of Azadirachta Indica and Vitamin E exhibited hepatoprotective effects on the Wistar rats that were subjected to Acetaminophen. Key words: Azadirachta Indica leaf extract, Vitamin E, hepatoprotective Paracetamol, Wistar rats.

Crocin Possesses Excellent Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Mice

Background: Acetaminophen (APAP) is a common analgesic and antipyretic medicine that can lead to acute liver injury at high doses. Crocin, a Crocus sativus’ ingredient, has potent antioxidant effects. Objectives: This study examined the protective effects of crocin against APAP-induced oxidative stress in mice. Methods: In this study, 56 mice were randomly divided into seven groups (n = 8 per group), including the negative (normal saline, 10 mL/kg) and positive (oral normal saline for five days + a single dose of APAP (300 mg/kg) on day 6th) control groups. The third group (NAC) received normal saline for up to five days, and on the 6th day, immediately after the administration of acetaminophen, received NAC (50 mg/kg). Groups fourth to sixth received respectively 12.5, 25, and 50 mg/kg of crocin (orally for six days), followed by a single dose of APAP (300 mg/kg) on 6th day. The last group received crocin (50 mg/kg) for six days. Then 24 h after the last injection, the animals were sacrificed, and samples were collected for biochemical and histopathological evaluations. Results: The levels of ALT, AST, and MDA increased, and the activity of CAT, GSH, and GPX decreased in the APAP-treated group compared to the control group. In APAP-treated groups, the administration of crocin decreased the serum levels of AST, ALT, and MDA and increased the activity of CAT, GSH, and GPX. Histopathological evaluations confirmed the above findings. Conclusions: According to our results, it seems that crocin has a protective effect against acetaminophen-induced liver toxicity and can be used as a therapeutic agent to treat APAP-induced hepatotoxicity.

S2846 Herpes Simplex Virus Hepatitis Causing Fulminant Liver Failure in a Non-Pregnant Woman

Introduction: HSV hepatitis is a rare cause of acute liver failure resulting in high morbidity and mortality with 74% progressing to death or liver transplant. Diagnosis is often delayed due to nonspecific symptoms, with the presence of characteristic rash in less than 50%. We present the case of a previously healthy non-pregnant woman who presented with acute liver failure from HSV-2 infection requiring transplant. Case Description/Methods: A 37-year-old woman presented to the ER with a 2-week history of fever, chills, and fatigue. She had been using acetaminophen 1 g q 3-4 hours for 1 week and reported longstanding alcohol use. She had normal mentation and no visible skin rashes. Labs showed ALT 3000, AST 5070, bilirubin 3.0, ALP 962. INR was 1.38 with an undetectable acetaminophen level. Tests for SARS-CoV-2, influenza, and Streptococcus were negative. She was started on N-acetylcysteine and transferred for consideration of liver transplant due to presumed acetaminophen-induced liver toxicity. On arrival the patient was alert but confused and unable to give an accurate history. Exam showed no oral, body or vaginal rash. Viral serologies showed CMVPCR -, EBV detected < 500, HIVRNA -, HCVRNA and HBVDNA -, HSV1 ND, HSV2 detected. Acyclovir (IV 10 mg/kg, 3 times/day) was started. Over 24 hours, mental status continued to decline requiring intubation. Liver biopsy revealed 70% submassive non-zonal necrosis with mixed portal inflammation and diffuse microvesicular steatosis, with no viral cytopathic effect. She underwent an uncomplicated orthotopic liver transplantation the next day. Explanted liver pathology showed submassive hepatic necrosis with staining positive for HSV. She continued on iv acyclovir and was discharged home. HSV remains detectable 25 days following transplant. At follow up patient described a diffuse macular rash which was present and resolved for 36 hours prior to hospital presentation. Discussion: This case illustrates the insidious onset and rapid clinical deterioration that can occur with HSV hepatitis. Given a high mortality rate, empiric initiation of IV acyclovir should be considered in patients with quantifiable HSV viremia and a viral prodrome. Our patient's non-characteristic rash resolved prior to evaluation, masking clinical suspicion for HSV hepatitis in the setting of acetaminophen and alcohol use. Patients may have clinical and histologic features suggesting drug-induced liver injury;thus, a broad differential diagnosis is key for early recognition and effective treatment.

Hepatoprotective role of Azadirachta Indica and Vitamin E in acetaminophen induced liver toxicity in Wistar rats

Aim To study the comparative effect of acetaminophen with aqueous Neem leaf extract (Azadirachta Indica) and vitamin E mediated liver toxicity on the basis of liver enzymes. Methods: A total of sixty (60) Wistar rats of either sex were divided equally into four groups. Each groupwas made up of 15 animals. Group A was the control group. Animals in Group B were treated with a single oral dose of 2 mg / kg b / w Paracetamol. Group C animals with 500 mg / kg b / w oral Neem extract for 15 days with oral administration of 2 mg / kg b / w oral Paracetamol. In Group D, animals received the same dose of Paracetamol and 100 mg / kg b / w intra-peritoneal vitamin E for 15 days, respectively. The liver enzymes ALT,AST, and ALP were then evaluated. Data was analyzed using SPSS Version 20.0 with level of significance being kept at p-value ≤0.05 Results: In the 4 groups, The ALT values were 22.8 (Group A), 100 (Group B), 29.11 (Group C), and 31.16 U/L (Group D). The AST values were 25 (Group A), 40 (Group B), 20 (Group C), and 15 (Group D) U/L. The ALP values were 220 (Group A), 445 (Group B), 242 (Group C), and 244 (Group D) U/L. There was significant increase in liver enzymes were found in Group B after induction of Paracetamol toxicity, however, hepatoprotective effects could be seen in the intervention Group C and D Conclusion: Azadirachta Indica and Vitamin E showed hepatoprotective effects on the Wistar rats that were subjected to Paracetamol Key words: Azadirachta Indicaleaf extract, Vitamin E, Paracetamol, Wistar rats

The effects of mitochondrial transplantation in acetaminophen-induced liver toxicity in rats

AimsAcetaminophen (APAP) toxicity is one of the leading causes of acute liver injury-related death and liver failure worldwide. In many studies, mitochondrial dysfunction has been identified as an important cause of damage in APAP toxicity. Therefore, our study aimed to investigate the possible effects of mitochondrial transplantation on liver damage due to APAP toxicity. Main methodsAPAP toxicity model was implemented by administering a toxic dose of APAP. To demonstrate the efficiency of mitochondria transplantation, it was compared with N-acetylcysteine (NAC) application, which is now clinically accepted. Mitochondrial transplantation was carried out by delivering mitochondria to the liver via the portal circulation, which was injected into the spleen. In our study, the rats were randomly divided into 6 groups as Sham, APAP, Control 1, APAP+mito, Control 2, and APAP+NAC. In the end of the experiment, histological and biochemical analysis were performed and the biodistribution of the transplanted mitochondria to target cells were also shown. Key findingsSuccessful mitochondrial transplantation was confirmed and mitochondrial transplantation improved the liver histological structure to a similar level with healthy rats. Moreover, plasma ALT levels, apoptotic cells, and total oxidant levels were decreased. It was also observed that NAC treatment increased GSH levels to the highest level among the groups. However, mitochondrial transplantation was more effective than NAC application in terms of histological and functional improvement. SignificanceIt has been evaluated that mitochondrial transplantation can be used as an important alternative or adjunctive treatment method in liver damage caused by toxic dose APAP intake.

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.

Evaluation of the hepatoprotective effect of methanolic extract of Caulerpa lentillifera against acetaminophen-induced liver toxicity in juvenile zebrafish (Danio rerio)

Background: Liver injury is a common reason for drugs to be withdrawn from the market. Treatment options for common liver disease are limited, and therapy with modern medicines may lack effectiveness. Caulerpa lentillifera may have strong antioxidant systems that protect the plant from oxidative damage caused by the environment.Objectives: The main objective of this study was to evaluate the hepatoprotective effect of the methanolic extract of C. lentillifera against acetaminophen-induced liver toxicity in juvenile zebrafish (Danio rerio). Methods: Juvenile zebrafish (aged 1–3 months) were exposed to 10 mikromolar and 25 mikromolar acetaminophen (N-acetyl-p-aminophenol; APAP) to induce liver damage. C. lentillifera methanolic extracts (0.01 mg/L, 0.02 mg/L and 0.03 mg/L), were concomitantly added to individual tanks containing 0.01 M or 0.025 M APAP. The positive control group was treated with N-acetylcysteine/NAC (0.01 M) and silymarin (0.01 mg/L, 0.02 mg/L and 0.03 mg/L). Hematoxylin and Eosin (H&amp;E) staining revealed the extent of liver injury through the presence of hepatic necrosis, vacuolization, leukocyte infiltration, and ballooning. The antioxidant mechanism of hepatoprotective activity was assessed by a DPPH free radical scavenging assay.Result: C. lentillifera extracts reduced the mortality of juvenile zebrafish when simultaneously exposed to APAP. Upon histopathological examination of the liver tissue of juvenile zebrafish, the group treated with the 0.01 M APAP together with the highest concentration of C. lentillifera extract showed minimal liver injury compared to the groups exposed 0.025 M APAP. However, the DPPH free radical scavenging assay performed using 24–36 mg/mL C. lentillifera extracts showed a minimal effect on the free radical scavenging activity.Conclusion: The histopathological analysis of the liver showed that C. lentillifera extract prevented the progression of liver damage caused by APAP. The results of DPPH free radical scavenging assay indicated that the hepatoprotective activity of C. lentillifera extract might have other antioxidant mechanisms aside from free radical scavenging. In order to effectively assess the improvement in the survival rate of juvenile zebrafish, longer exposure in the treatments is recommendedKeywords: C. lentillifera; juvenile zebrafish; hepatoprotective; drug-induced liver injury (DILI)

Nigella sativa's protective effect in acetaminophen induced liver toxicity in mice

Acetaminophen has contributed to acute liver failure disease in more than half of the USA and Britain but as an analgesic and antipyretic it is very effective. For many decades in Europe, Middle East and Africa, Nigella sativa has been used for various medical purposes, it is part of the botanical family Ranunculaceae of&#x0D; &#x0D; Gently sloping plants, and is called black cumin seed., Nigella sativa conjugated sterols could be used as precursors to many hydrosoluble steroids for hemisynthesis. The aim of the Study is to examine the promising hepatoprotective effects of Nigella sativa against Acetaminopheninduce hepatotoxicity in mice in this experiment Forty adult male albino mice, incorporated in the experiment and Acetaminophenwas used to induce hepatotoxicity in a dose of 1 gm /kg by the oral route.&#x0D; A number of biochemical and histopathological tests have been used to evaluate liver damage and Nigella sativa protective effects. The result showed a significant protective effect of Nigella sativa against acetaminophenhepatotoxic effect as Nigella sativa in this study tended to normalize the serum levels of liver enzymes, and the protective effects observed clearly by the histopathological evaluation confirming that it effectively protected mouse livers against severe damage caused by acetaminophen. Conclusion in our study it shows that Nigella sativa have a very significant protective effects against acetaminophen induced liver toxicity which is recommended to be fully investigation on human especially to people on risk of acetaminophen liver toxicity

Prophylactic and Therapeutic Effect of Aqueous Stem Extract of Costus afer on Lipids and Atherogenic Profile of Albino Rats in Acetaminophen Induced Liver Toxicity

Background: Medicinal plants are widely used in Nigeria because they are believed to be effective in the treatment of various medical conditions and are also easily accessable with minimal side effect.&#x0D; Aim: This study evaluates the prophylactic and therapeutic effects of different doses (200 mg/kg, 400 mg/kg and 800 mg/kg body weight) of Costus afer on lipid profile of 50 male albino rats.&#x0D; Methodology: The research study was divided into 2 phases with 25 rats used for each phases. The 25 rats used for each phase were randomly selected into 5 groups with each group containing 5 rats. The rats used for the prophylactic phase were induced with 800 mg/kg body weight paracetamol for liver toxicity after administration of the various concentrations of aqueous stem extract of C. afer for 28 days while those used during the therapeutic phase were administered with the various concentrations of aqueous stem extract of C. afer following confirmation of liver toxicity using 800 mg/kg body weight acetaminophen. The effect of the aqueous extract was assessed by measuring the serum concentration of total cholesterol, triglycerides and high density lipoprotein using Randox reagent, while low density lipoprotein was calculated from the other parameters. Atherogenic ratios were also computed. The result obtained from the experiment was subjected to statistical analysis using Graph pad prism version 5.3 and values were considered significant at p&lt;0.05.&#x0D; Results: Total cholesterol, triglycerides and LDL levels were significantly (p&lt;0.05) reduced and HDL significantly increased in the treatment groups (prophylactic and therapeutic phases) compared to the positive control. When both phases were compared, total cholesterol and triglycerides showed significant (p&lt;0.05) difference in concentration in groups fed with 400 mg/kg, 200 mgkg while LDL-C showed significant (p&lt;0.05) variation between the two phases only at 400 mg/kg body weight. The extracts were also found to significantly (p&lt;0.05) reduce the atherogenic status of the albino rats in both phases of treatment and between each treatment phase.&#x0D; Conclusion: Findings from this study suggest that Costus afer possesses the ability to regulate paracetamol induced dyslipidaemia and improve the anti-atherogenic status of treated albino rats.

Nigella sativa's protective effect in acetaminophen induced liver toxicity in mice

Acetaminophen has contributed to acute liver failure disease in more than half of the USA and Britain but as an analgesic and antipyretic it is very effective. For many decades in Europe, Middle East and Africa, Nigella sativa has been used for various medical purposes, it is part of the botanical family Ranunculaceae of Gently sloping plants, and is called black cumin seed., Nigella sativa conjugated sterols could be used as precursors to many hydrosoluble steroids for hemisynthesis. The aim of the Study is to examine the promising hepatoprotective effects of Nigella sativa against Acetaminopheninduce hepatotoxicity in mice in this experiment Forty adult male albino mice, incorporated in the experiment and Acetaminophenwas used to induce hepatotoxicity in a dose of 1 gm /kg by the oral route. A number of biochemical and histopathological tests have been used to evaluate liver damage and Nigella sativa protective effects. The result showed a significant protective effect of Nigella sativa against acetaminophenhepatotoxic effect as Nigella sativa in this study tended to normalize the serum levels of liver enzymes, and the protective effects observed clearly by the histopathological evaluation confirming that it effectively protected mouse livers against severe damage caused by acetaminophen. Conclusion in our study it shows that Nigella sativa have a very significant protective effects against acetaminophen induced liver toxicity which is recommended to be fully investigation on human especially to people on risk of acetaminophen liver toxicity

The Bile Acid Receptor GPBAR1 Modulates CCL2/CCR2 Signaling at the Liver Sinusoidal/Macrophage Interface and Reverses Acetaminophen-Induced Liver Toxicity.

Drug-induced liver injury caused by acetaminophen (acetyl-para-aminophenol [APAP]) is the main cause of acute liver failure and liver transplantation in several Western countries. Whereas direct toxicity exerted by APAP metabolites is a key determinant for early hepatocytes injury, the recruitment of cells of innate immunity exerts a mechanistic role in disease progression, determining the clinical outcomes. GPBAR1 is a G protein-coupled receptor for secondary bile acids placed at the interface between liver sinusoidal cells and innate immunity. In this report, using genetic and pharmacological approaches, we demonstrate that whereas Gpbar1 gene deletion worsens the severity of liver injury, its pharmacological activation by 6β-ethyl-3a,7b-dihydroxy-5b-cholan-24-ol rescues mice from liver injury caused by APAP. This protective effect was supported by a robust attenuation of liver recruitment of monocyte-derived macrophages and their repolarization toward an anti-inflammatory phenotype. Macrophage depletion by gadolinium chloride pretreatment abrogated disease development, whereas their reconstitution by spleen-derived macrophage transplantation restored the sensitivity to APAP in a GPBAR1-dependent manner. RNA sequencing analyses demonstrated that GPBAR1 agonism modulated the expression of multiple pathways, including the chemokine CCL2 and its receptor, CCR2. Treating wild-type mice with an anti-CCL2 mAb attenuated the severity of liver injury. We demonstrated that negative regulation of CCL2 production by GPBAR1 agonism was promoter dependent and involved FOXO1. In conclusion, we have shown that GPBAR1 is an upstream modulator of CCL2/CCR2 axis at the sinusoidal cell/macrophage interface, providing a novel target in the treatment of liver damage caused by APAP.

Genistein protects against acetaminophen-induced liver toxicity through augmentation of SIRT1 with induction of Nrf2 signalling

Previous studies suggest that genistein protects liver from acetaminophen (APAP)-induced injury, however, the detailed mechanism of the process is still incompletely. Therefore, present study was to investigate the potential mechanism of the genistein mediated protection against APAP-induced hepatotoxicity. As shown, supplementation with 150 mg/kg genistein greatly alleviated the increase in serum alanine aminotransferase (ALT) activity, aspartate aminotransferase (AST) activity, hepatic malondialdehyde (MDA) contents, and reversed the decrease in hepatic GSH levels in response to overdose APAP. At the same time, hepatic SIRT1 protein and activity were markedly upregulated in mouse receiving genistein. However, the amelioration was almost abolished by the knockdown of hepatic SIRT1 expression using lentivirus carrying specific shRNA targeting SIRT1. These results were further validated by histopathology examination. Moreover, depletion of hepatic SIRT1 prevented the accumulation of Nrf2 in nucleus and the upregulation of the antioxidant gene expression in the presence of genistein and/or APAP. Concomitantly, the induced mRNA expression of UDP-glucuronosyltransferases (UGTs) by genistein was largely dependent on the SIRT1 expression and activity. Together, our results support the notion that the strong elevation of SIRT1 expression and activity may represent a potential mechanism of protection against APAP-induced liver injury by genistein.

Chlorella sp. Protective Effect on Acetaminophen-Induced Liver Toxicity in ICR Mice.

Background:A Chlorella sp. (CLC) has a health supplement in health effects including an ability to treat cancer. The Chlorella sp. Ability to reduce acetaminophen-induced liver injury is still unknown. The hepatoprotective function of CLC was determined in an APAP-induced liver injury mouse model.Methods:Male ICR mice were randomly divided into normal control, APAP, APAP + Sm (silymarin) and APAP + CLC (0.2%, 0.5% and 1%) groups. The glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), Albumin, and BUN plasma activities were detected using blood biochemistry assay. The hepatic tissue GOT, GPT, superoxide dismutase (SOD) and catalase (CAT) activity were also detected. Lipid peroxidation, MDA, protein expression levels were examined.Results:The results showed that the 1% CLC supplementation group and Silymarin (Sm) could significantly alleviate increased serum GOT, GPT and BUN, and the decreased serum Albumin. At the same time, the increased hepatic tissue GOT and GPT activities were alleviated as well as MDA. Enhanced SOD and CAT protein expression levels were increased in APAP-induced liver injury. Lipofuscin and hepatic veins cups disappeared in the Sm and 1% CLC supplementation groups shown with H&E staining.Conclusions:Therefore, CLC probably could develop hepatoprotective products against chemical-induced liver damage.