Search Results (19)

Paracetamol (APAP) overdose is the leading cause of drug-induced liver injury, leading to acute liver failure. However, the role of concurrent acute or chronic ethanol ingestion in this context requires further clarification. In this study, we investigated the effects of acute and chronic ethanol ingestion on APAP-induced hepatotoxicity. Male C57BL/6 mice were randomly allocated into four groups: control (C; water 2×/day for 7 days); APAP (single dose of APAP, 500 mg/kg); acute ethanol (AE; a single ethanol dose—10 mL/kg, and one hour later an overdose of APAP—500 mg/kg); chronic ethanol (CE; ethanol—10 mL/kg, 2×/day for 7 days; and on the last day, an overdose of APAP—500 mg/kg). The results showed that AE induced heightened liver damage, increased necrotic area, and elevated levels of ALT, AST, TBARS, and oxidized glutathione compared to the control group. The AE group exhibited diminished glutathione availability and elevated CYP2E1 levels compared to the other groups. CE maintained a hepatic profile similar to that of the control group in terms of necrosis index, ALT and AST levels, GSH/GSSG ratio, and CYP2E1 activity, along with the upregulation of gene expression of the glucuronidation enzyme compared to the APAP group. Proteomic analysis revealed that the AE protein profile closely resembled that of the APAP group, whereas the C and CE groups were clustered together. In conclusion, ethanol consumption differentially modulated APAP overdose-induced liver damage. Acute consumption exacerbated hepatotoxicity, similar to an APAP overdose alone, whereas chronic consumption appeared to mitigate this injury, at least within the parameters assessed in this study. Full article

Background/Objective: Hepatic drug intoxication is becoming increasingly common with the increasing use of chronic medications. Piperine has emerged as a promising alternative for protecting the liver against drug-induced injury. We evaluated the prophylactic effects of piperine in C57BL/6 mice with an acute liver injury induced by a paracetamol (APAP) overdose. Methods: Piperine was administered at a dose of 20 mg/kg (P20) or 40 mg/kg (P40) for eight consecutive days before the animals were exposed to a hepatotoxic dose of paracetamol (500 mg/kg). The animals were euthanized 3 h after the paracetamol overdose. Results: The prophylactic treatment with piperine (P20 and P40) maintained the levels of alanine aminotransferase (ALT) and the biomarkers of oxidative damage (TBARS and carbonylated proteins), which were statistically similar to those for the control group. The extent of hepatocyte necrosis and TNF-α (tumor necrosis factor-alpha) levels were lower than those in the group exposed to liver injury (APAP group). Piperine modulated the gene expression of CYP2E1 (cytochrome P4502E1) and the inflammasome pathway (NLRP3, CASP-1, IL-1β, and IL-18), which play a crucial role in the inflammatory response. In the P40 group, the degree of hepatic hyperemia was similar to that in the control group, as was the increase in metalloproteinase 9 (MMP-9) activity. Conclusion: Piperine has demonstrated beneficial and promising effects for the prevention of liver injury resulting from paracetamol-induced drug intoxication. Full article

NSAIDs and paracetamol are commonly used as antipyretic treatments, which may impair renal and hepatic function, respectively. Both organ systems are also negatively affected by COVID-19. In two retrospective case–control studies, we investigated whether COVID-19 is a risk factor for the development of renal or hepatic function impairment after NSAID and paracetamol use, respectively. In the NSAID study, we defined cases as patients with a decrease of ≥15% in the estimated glomerular filtration rate (eGFR). We matched them using a 1:2 ratio with controls who did not show a decrease in the eGFR. For the paracetamol study, we matched patients with ALT or ALP ≥ 3x, the upper limits of normal, using a 1:3 ratio with controls whose liver enzymes did not increase. In both studies, we selected demographic data, comorbidities, drug doses, and laboratory values as predictors in addition to SARS-CoV-2 test status. We applied different machine learning models to predict renal and hepatic function impairment. From the cohort of 12,263 unique adult inpatients, we found 288 cases of renal function impairment, which were matched with 576 controls, and 213 cases of liver function impairment, which were matched with 639 controls. In both case–control studies, testing positive for SARS-CoV-2 was not an independent risk factor for the studied adverse drug effects. Full article

Silymarin, derived from Silybum marianum, has been used in traditional medicine for various ailments. In this study, the cardioprotective and hepatoprotective effects of silymarin against paracetamol-induced oxidative stress were examined in 28 male Swiss Webster mice, divided into four groups and treated for 7 days (via the oral route) with (a) saline 1 mL/kg (control group), (b) saline 1 mL/kg + single dose of paracetamol 110 mg/kg on the 7th day; (c) silymarin 50 mg/kg; and (d) silymarin 50 mg/kg + single dose of paracetamol 110 mg/kg on the 7th day. In vitro and in vivo antioxidant activity together with liver enzyme activity were evaluated. Histopathological and immunohistochemical assessment was performed. Silymarin mitigated paracetamol-induced liver injury by reducing oxidative stress markers such as lipid peroxidation and restoring antioxidant enzyme activity. Silymarin treatment resulted in a significant decrease in liver enzyme levels. Reduced necrosis and inflammatory infiltrate in liver tissues of silymarin-treated groups were detected as well. Immunohistochemical analysis demonstrated reduced expression of inflammatory markers (COX2, iNOS) and oxidative stress marker (SOD2) in the liver tissues of the silymarin-treated groups. Similar trends were observed in cardiac tissue. These results suggest that silymarin exerts potent hepatoprotective and cardioprotective effects against paracetamol-induced oxidative stress, making it a promising therapeutic agent for liver and heart diseases associated with oxidative damage. Full article

Paracetamol or acetaminophen (PAC) is a commonly used analgesic and antipyretic drug. It has been shown that overdoses beyond the therapeutic range can cause hepatotoxicity and acute liver injury. The most common cause of drug-induced liver injury (DILI) in Saudi Arabia and worldwide is paracetamol overdose. Fucoxanthin (FUC) is an allenic carotenoid that is found in edible brown seaweeds, and it has antioxidant and anti-inflammatory effects. Several studies have shown the potential therapeutic effects of FUC in diabetes, cancers, and inflammatory disorders. This study aims to investigate the protective effect of FUC against PAC-induced acute liver injury in rats. FUC was administered (100, 200, and 500 mg/kg, p.o.) for 7 days, and then the liver injury was induced by the administration of PAC (2000 mg/kg, oral). Blood and liver tissue samples were collected from PAC-positive untreated, treated, and negative control rats. Biochemical and inflammatory parameters in the blood were measured. In addition, RT-PCR, Western blotting, and immunohistochemistry were performed for liver tissue. The serum levels of liver biomarkers (ALT, AST, and ALP) increased after PAC-induced liver toxicity; FUC-treated rats showed lower levels compared to the positive control. There was an increase in the expression of TNF-α, IL-1, IL-6, NF-kB, INF-γ, and iNOS and a decrease in IL-10, IL-22, and IL-10R expression after the FUC treatment of injured liver rats. For the hepatic inflammation and PAC-toxicity-induced oxidative stress genes and proteins, FUC-treated rats (100, 200, and 500 mg/kg) showed a reduction in the expression of oxidative stress genes. These results showed that FUC protected the liver against PAC-induced injury through antioxidant and anti-inflammatory actions. However, further clinical studies are required to confirm the findings. Full article

Acetaminophen (APAP) is a widely used drug, but overdose can cause severe acute liver injury. The first reports of APAP hepatotoxicity in humans were published in 1966, shortly after the development of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as the first biomarkers of liver injury as opposed to liver function. Thus, the field of liver injury biomarkers has evolved alongside the growth in APAP hepatotoxicity incidence. Numerous biomarkers have been proposed for use in the management of APAP overdose patients in the intervening years. Here, we comprehensively review the development of these markers from the 1960s to the present day and briefly discuss possible future directions. Full article

Suaeda vermiculata Forssk. ex JF Gmel. (SV), a traditional known plant, has shown in vitro cytotoxic activity against HepG2 and HepG-2/ADR (doxorubicin-resistant cells) liver cell carcinoma cell lines, as well as hepatoprotection against paracetamol and carbon tetrachloride (CCl4)-induced liver injury. The current study evaluated the protective effect of SV, administered against N-diethylnitrosamine (NDEA)-induced HCC in rats. The possible modulatory effect of SV on the PI3K/HIF-1α/c-MYC/iNOS pathway was investigated. Sixty male adult albino rats (200 ± 10 g) were equally classified into five groups. Group I served as a control; Group 2 (SV control group) received SV (p.o., 200 mg/kg body weight); Group 3 (NDEA-administered rats) received freshly prepared NDEA solution (100 mg/L); and Groups 4 and 5 received simultaneously, for 16 weeks, NDEA + SV extract (100 and 200 mg/kg, orally). NDEA-treated rats displayed significant increases in serum levels of AFP, CEA, PI3K, malondialdehyde (MDA), epidermal growth factor receptor (EGFR), and vascular endothelial growth factor (VEGFR), with increased liver tissue protein expression of fibrinogen concomitant and significantly decreased concentrations of antioxidant parameters (catalase (CAT), superoxide dismutase (SOD), and reduced glutathione (GSH)) in comparison to normal rats. On the flip side, AFP, CEA, PI3K, MDA, EGFR, and VEGFR serum levels were significantly reduced in rats that received NDEA with SV, both at low (SV LD) and high (SV HD) doses, accompanied by significant improvements in antioxidant parameters compared to the NDEA-treated group. Conclusions: SV possesses a significant hepatoprotective effect against NDEA-induced HCC via inhibiting the PI3K/HIF-1α/c-MYC/iNOS pathway, suggesting that SV could be a promising hepatocellular carcinoma treatment. Full article

Sphingolipids are exceptionally diverse, comprising hundreds of unique species. The bulk of circulating sphingolipids are synthesized in the liver, thereby plasma sphingolipid profiles represent reliable surrogates of hepatic sphingolipid metabolism and content. As changes in plasma sphingolipid content have been associated to exposure to drugs inducing hepatotoxicity both in vitro and in rodents, in the present study the translatability of the preclinical data was assessed by analyzing the plasma of patients with suspected drug-induced liver injury (DILI) and control subjects. DILI patients, whether intrinsic or idiosyncratic cases, had no alterations in total sphingoid base levels and profile composition compared to controls, whereby cardiovascular disease (CVD) was a confounding factor. Upon exclusion of CVD individuals, elevation of 1-deoxysphingosine (1-deoxySO) in the DILI group emerged. Notably, 1-deoxySO values did not correlate with ALT values. While 1-deoxySO was elevated in all DILI cases, only intrinsic DILI cases concomitantly displayed reduction of select shorter chain sphingoid bases. Significant perturbation of the sphingolipid metabolism observed in this small exploratory clinical study is discussed and put into context, in the consideration that sphingolipids might contribute to the onset and progression of DILI, and that circulating sphingoid bases may function as mechanistic markers to study DILI pathophysiology. Full article

In the current investigation, Annona muricata Linn. lyophilized fruit pulp powder was evaluated for its hepatoprotective activity induced by paracetamol or acetaminophen (APAP). Male Sprague Dawley rats were orally pre-treated for 15 days with A. muricata lyophilized fruit pulp powder at low (1 g/kg b.wt) and high doses (2 g/kg b.wt). Silymarin (100 mg/kg) was administered as the standard drug. Hepatotoxicity was induced using APAP, in a single oral administration of 2.5 g/kg body weight dosage on the 15th day. Aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were elevated in the APAP group but were found to be significantly reduced in the pre-treated groups in a dose-dependent manner. APAP administration brought down the serum total protein and albumin levels significantly. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase were reduced in the APAP administration; further, the reduced glutathione pool in the tissue was also diminished significantly. However, with the administration of Annona lyophilized fruit pulp powder, the level of antioxidant parameters was near normal. A significant increase in lipid peroxidation was observed in the APAP group, while the silymarin, AML, and AMH groups exhibited resistance to lipid peroxidation (LPO), as evident from lower levels of LPO generated. Histopathological examination also revealed considerable tissue damage in the APAP alone treatment group, which was not devastating in the silymarin, AML, and AMH groups. Altogether, the study concludes that the lyophilized fruit pulp of A. muricata is protective against APAP-induced liver injury in rats by modulating the hepatic redox systems. Full article

Glycogen, the branched polymer of glucose is found mainly in the liver and muscle in mammals. Along with several other proteins, glycogen forms separate cellular organelles, and particles in cells. Glycogen particles in the liver have a special metabolic and also regulatory connection to the intracellular endomembrane system, particularly the endoplasmic reticulum. This connection is part of the organelle homeostasis in hepatocytes and forms a “glycogenoreticular system”. The actual size of hepatic glycogen stores and the rate of glycogenolysis determines several essential liver-specific metabolic processes, such as glucose secretion for the maintenance of blood glucose levels or the glucuronidation of certain vital endo-, and xenobiotics, and are also related to liver antioxidant defense. In starvation, and in certain physiological and pathological states, where glycogen stores are depleted, functions of the glycogenoreticular system are altered. The starvation-induced depletion of hepatic glycogen content changes the biotransformation of various endo- and xenobiotics. This can be observed especially in acute DILI (drug-induced liver injury) due to paracetamol overdose, which is the most common cause of acute liver failure in the West. Full article

Background: Curcumin is a natural product obtained from the rhizome of Curcuma longa. Rosemary (Rosmarinus officinalis) is a medicinal and aromatic plant that is widely spread in the Mediterranean region. Both Curcumin and rosemary essential oil are natural products of high medicinal and pharmacological significance. The hepatoprotective effect of both natural products is well-established; however, the mechanism of such action is not fully understood. Thus, this study is an attempt to explore the hepatoprotective mechanism of action of these remedies through their effect on MEK and ERK proteins. Furthermore, the effect of rosemary essential oil on the plasma concentration of curcumin has been scrutinized. Materials and methods: The major constituents of REO were qualitatively and quantitatively determined by GC/MS and GC/FID, respectively. Curcumin and rosemary essential oil were given to mice in a pre-treatment model, followed by induction of liver injury through a high dose of paracetamol. Serum liver enzymes, lipid peroxidation, antioxidant activities, the inflammatory and apoptotic biomarkers, as well as the MEK and ERK portions, were verified. The plasma levels of curcumin were determined in the presence and absence of rosemary essential oil. Results: The major constituents of REO were 1,8-cineole (51.52%), camphor (10.52%), and α-pinene (8.41%). The results revealed a superior hepatoprotective activity of the combination when compared to each natural product alone, as demonstrated by the lowered liver enzymes, lipid peroxidation, mitigated inflammatory and apoptotic biomarkers, and enhanced antioxidant activities. Furthermore, the combination induced the overexpression of MEK and ERK proteins, providing evidence for the involvement of this cascade in the hepatoprotective activity of such natural products. The administration of rosemary essential oil with curcumin enhanced the curcuminoid plasma level. Conclusion: The co-administration of both curcumin and rosemary essential oil together enhanced both their hepatoprotective activity and the level of curcumin in plasma, indicating a synergistic activity between both natural products. Full article

Drug-induced liver injury (DILI) is uncommon but potentially lethal. Over 6 years, 2533 children with acute liver disease were identified in our center, 48 of which suffered from toxic hepatitis, and 40 exhibited DILI (22 paracetamol-related, 14 albendazole-related). The most affected children were in the 13–17-year-old age group. The mean time between drug ingestion and disease diagnosis was 25.4 h for paracetamol-related DILI and 21.6 days for the albendazole-related group. Clinical features were mostly gastrointestinal, jaundice being reported in 30% of the cases. Regarding the type of liver injury, for 70% of the patients it was hepatocellular (mostly paracetamol toxicity), for 11% cholestatic, and for 19% mixed (albendazole-related). The mean initial ALT value was 1020 U/L for all DILIs. Coagulopathy was only identified for the acetaminophen-related group. The median number of hospitalization days was 6.9 for DILI related to acetaminophen ingestion, compared with 7 for the idiosyncratic pattern. When applying the DILI severity index, 81% of the patients were categorized as having a mild hepatic ailment, while 19% had a moderate–severe or severe disease. No deaths were reported in the study group. The diagnosis of DILI involves the exclusion of other causes of liver injury; therefore, it is considered one of the most challenging diagnoses in hepatology. Full article

To examine antioxidant capacity and the hepatoprotective effect of carob pulp flour, microwave-assisted extraction was performed. The influence of ethanol concentration (0–40% w/w), extraction time (5–25 min) and irradiation power (400–800 W) on DPPH, FRAP and ABTS antioxidant activity of carob pulp flour extract was evaluated. The strongest influence was that of the ethanol concentration, followed by extraction time. Optimal process parameters for maximizing total antioxidant activity were determined, using response surface methodology: ethanol concentration 40%, time 25 min and power 800 W. Carob extract obtained at optimal conditions (CE) was analyzed in vivo using a paracetamol-induced hepatotoxicity model in mice. Treatment with CE attenuated the parameters of liver injury, especially aspartate and alanine aminotransferase activity, and prevented paracetamol-induced increase in malondialdehyde levels. Pretreatment with CE reversed the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase enzymes after the high dose of paracetamol in the liver. Hepatotoxicity induced using a toxic dose of paracetamol was also seen through histopathological alterations, which were significantly reduced in the groups treated with CE prior to paracetamol. Still, the number of Kupffer cells and macrophages did not differ among groups. Finally, pretreatment of mice with CE and paracetamol significantly decreased the expression of cytochrome P450 2E1 (CYP2E1) in hepatocytes. Full article

Macrophages are activated during the early phase of paracetamol-induced liver injury (PLI). [¹⁸F]GE180 is a radiolabeled ligand that recognizes the macrophage translocator protein (TSPO). In this study, we evaluated the feasibility of a TSPO-specific radiotracer in a rat model of PLI. A rat model of liver injury was induced by intraperitoneal administration of paracetamol. [¹⁸F]GE180 positron emission tomography (PET) images were obtained after 24 h. The maximal and mean standardized uptake values (SUV_max and SUV_av) of the liver and serum biomarker levels were examined. The TSPO expression level was examined using real-time polymerase chain reaction and Western blot analysis. [¹⁸F]GE180 hepatic uptake in the PLI group was significantly higher than that in the control group (SUV_max p = 0.001; SUV_av p = 0.005). Both mRNA and protein TSPO expression levels were higher in the PLI group. The mRNA expression level of TSPO was significantly correlated with [¹⁸F]GE180 hepatic uptake in both groups (SUV_max p = 0.019; SUV_av p = 0.007). [¹⁸F]GE180 hepatic uptake in the PLI group showed a significant positive correlation with ALT₂₄ and ALT₄₈ (ALT₂₄ p = 0.016; ALT₄₈p = 0.002). [¹⁸F]GE180 enabled visualization of PLI through TSPO overexpression. Our results support the potential utility of hepatic uptake by TSPO-PET as a non-invasive imaging biomarker for the early phase of PLI. Full article

Background and Objectives: Over-the-counter availability and a good safety profile make paracetamol one of the most common analgesics in developed countries but also the leading cause of liver failure due to overdose. The objectives of the study were to identify modifiable risk factors for severe hepatotoxicity following paracetamol overdose in adults. Materials and Methods: A retrospective cohort study involved the consecutive adult patients hospitalized in a toxicological center over a period of seven years due to paracetamol overdose. Complete medical datasets of laboratory and anamnestic variables were analyzed and validated by means of logistic regression model. Results: A total of 185 patients entered the study, including 25 individuals who developed severe hepatotoxicity (plasma aminotransferases levels above 1000 UI/L) and 31 individuals with mild to moderate liver injury (plasma aminotransferases levels above upper normal range, but below 1000 UI/L). In the univariable analysis, significant hepatotoxicity risk factors were male gender, alcohol abuse, an ingested paracetamol dose, and a timespan from ingestion to hospital admission. The later one was the only significant risk factor in the multivariable model (adjusted odds ratio 1.08; 95% CI: 1.03–1.12). Conclusions: A delay in hospital admission, resulting in a delayed administration of disease-specific treatment outweighs any other known risk factors of paracetamol-induced hepatotoxicity. Full article