Paracetamol-induced Hepatotoxicity Research Articles

Unveiling the molecular basis of paracetamol-induced hepatotoxicity: Interaction of N-acetyl-p-benzoquinone imine with mitochondrial succinate dehydrogenase

Background and aimN-acetyl-p-benzoquinoneimine (NAPQI), a toxic byproduct of paracetamol (Acetaminophen, APAP), can accumulate and cause liver damage by depleting glutathione and forming protein adducts in the mitochondria. These adducts disrupt the respiratory chain, increasing superoxide production and reducing ATP. The goal of this study was to provide computational proof that succinate dehydrogenase (SDH), a subunit of complex II in the mitochondrial respiratory chain, is a favorable binding partner for NAPQI in this regard. MethodMolecular docking, molecular dynamics simulation, protein-protein interaction networks (PPI), and KEGG metabolic pathway analysis were employed to identify binding characteristics, interaction partners, and their associations with metabolic pathways. A lipid membrane was added to the experimental apparatus to mimic the natural cellular environment of SDH. This modification made it possible to develop a context for investigating the role and interactions of SDH within a cellular ecosystem that was more realistic and biologically relevant. ResultThe molecular binding affinity score for APAP and NAPQI with SDH was predicted −6.5 and −6.7 kcal/mol, respectively. Furthermore, RMSD, RMSF, and Rog from the molecular dynamics simulations study revealed that NAPQI has slightly higher stability and compactness compared to APAP at 100 ns timeframe with mitochondrial SDH. ConclusionThis study serves to predict the mechanistic process of paracetamol toxicity by using different computational approaches. In addition, this study will provide information about the drug target against APAP hepatotoxicity.

A Comparison of the Protective Effect of Pyridoxine and N-Acetylcysteine in Paracetamol Induced Hepatotoxicity in Rats

Paracetamol is a common over the counter drug. Paracetamol-induced hepatotoxicity results in over 300,000 hospitalizations each year and accounts for up to 42% of all cases of acute liver failure. N-acetylcysteine (NAC) is a potential antidote to manage paracetamol toxicity. Objective: To investigate the effects of pyridoxine, alone and in combination with NAC in repairing paracetamol-induced liver damage in male Wister rats. Methods: A single oral dose of paracetamol (650 mg/kg) was administered to Wistar rats to induce hepatotoxicity. The hepato-protective effects of NAC at a dose 300 mg/kg, and pyridoxine (200 mg/kg) were evaluated using standard liver function tests and histopathological along with serum glutathione levels. Results: The administration of pyridoxine and NAC resulted in a significant decrease in AST, ALT, and total bilirubin levels and the reversal of histopathological changes. Conversely, administering NAC and pyridoxine in combination yielded significant changes except for the glutathione level. Conclusions: The study concluded that pyridoxine may be used as a potential hepatoprotective drug in paracetamol-induced hepatotoxicity. In combination with NAC, it showed protective effects in paracetamol-induced hepatoxicity.

Counteracting Paracetamol-Induced Hepatotoxicity with Black Shallot Extract: An Animal Model Investigation

Counteracting Paracetamol-Induced Hepatotoxicity with Black Shallot Extract: An Animal Model Investigation

Hepatoprotective Effects of a Chemically-Characterized Extract from Cistus ladanifer: In Vivo and in Silico Investigations

Background: Liver damage is indicated by histopathological and metabolic dysfunction. There has been increasing interest in natural hepatoprotective agents from medicinal herbs. The medicinal plant Cistus ladanifer widely used in phytotherapy was selected for this study. Objectives: The work aims to investigate the hepatoprotective effects of Cistus ladanifer leaf extracts in vivo against the paracetamol-induced hepatotoxicity mice and in silico using the docking method. The chemical composition of the extracts was also studied. Materials and methods: The paracetamol-induced hepatotoxicity mice were treated with aqueous and methanolic extracts of Cistus ladanifer at two doses of 150 and 300 mg/kg body. The serum levels of aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, urea, and creatinine in mice-induced hepatotoxicity were measured to evaluate the hepatoprotective activity of the extracts. The histopathological alterations were also investigated. The chemical profile of methanolic and aqueous C. ladanifer extracts was determined using GC-MS. The Human Cytochrome P450 2E1(CYP2E1) was presented as a protein target and the docking was studied using Maestro version 11.5 software developed by Schrodinger, LLC. Results: The administration of C. ladanifer extracts showed hepatic protection at an oral dose of 150 and 300 mg/kg for the aqueous extract and only at 150 mg/kg for the methanolic one. The aqueous extract at both doses and the methanolic extract at 150 mg/kg didn’t occur any biochemical or histological alterations. However, the methanolic extract showed hepatic toxicity at 300 mg/kg. Various compounds were identified in the methanolic and the aqueous extracts, probably responsible of the hepatoprotective activity. The in silico study has also shown that some molecules present in both extracts presented a good affinity in the active site of Cytochrome P450 2E1 (CYP2E1). Conclusion: The results deserve more attention as C. ladanifer can be considered a source of pharmacological compounds with hepatoprotective effects. Further detailed investigation is needed to deepen the study.

Flaxseed Lignan Alleviates the Paracetamol-Induced Hepatotoxicity Associated with Regulation of Gut Microbiota and Serum Metabolome.

This study examined the protective effect of flaxseed lignans on liver damage caused by an overdose of paracetamol (PAM). The findings demonstrated that administering 800 mg/kg/d flaxseed lignan prior to PAM significantly decreased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBi) levels, while it increased liver superoxide dismutase (SOD) and glutathione (GSH) levels in mice. Flaxseed lignan renovated the gut microbiota dysbiosis induced by PAM by promoting the proliferation of sulfonolipid (SL) producing bacteria such as Alistipes and lignan-deglycosolating bacteria such as Ruminococcus while inhibiting the growth of opportunistic pathogen bacteria such as Acinetobacter and Clostridium. Furthermore, flaxseed lignan modulated the serum metabolomic profile after PAM administration, specifically in the taurine and hypotaurine metabolism, phenylalanine metabolism, and pyrimidine metabolism. The study identified eight potential biomarkers, including enterolactone, cervonyl carnitine, acutilobin, and PC (20:3(5Z, 8Z, 11Z)/20:0). Overall, the results suggest that flaxseed lignan can alleviate PAM-induced hepatotoxicity and may be beneficial in preventing drug-induced microbiome and metabolomic disorders.

Protective Effect of Black Seed and Lettuce Oils Against Paracetamol-Induced Hepatotoxicity in Rats.

<b>Background and Objective:</b> The liver is one of the organs that play an essential role in the human body, including supporting metabolism, immune functions, digestive system, detoxification, storage of vitamins and other functions. This investigation aimed to study the protective effects of black seed and lettuce oil against hepatotoxicity as induced by paracetamol in experimental rats. <b>Materials and Methods:</b> Twenty male Sprague-Dawley albino rats weighing 150±5 g were divided randomly into four groups (5 rats each) and distributed as follows; 1st group was controlled negative (C -ve group), 2nd group controlled positive (orally administered with 500 mg/kg b.wt., paracetamol), 3rd and 4th groups were orally administered with black seed oil and lettuce oil at a dose of 1 mL/kg b.wt., each) as a preventive dose. All rats were sacrificed and blood was collected for biochemical analysis and then statistically analyzed. <b>Results:</b> The rat administered with black seed and lettuce oils enhanced body weight gain, food intake and feed efficiency ratio. Moreover, exhibited a significant reduction in the liver enzymes AST, ALT, ALP and TBIL. Meanwhile, black seed and lettuce oils significantly improved kidney functions, lipid profiles and some immune biomarkers including creatine kinase (CK), Creatine Kinase-MB (CK-MB) and Lactate Dehydrogenase (LDH). <b>Conclusion:</b> This study revealed that the oils of black seed (<i>Nigella sativa</i>) and lettuce (<i>Lactuca sativa</i>) have a protective role in improving body weight gain, food intake, feed efficiency ratio, liver enzymes, kidney functions, lipid profiles and some immune biomarkers against paracetamol-induced hepatotoxicity in experimental rats.

Ethanolic Extract of Citrus Sinensis Peel Markedly Mitigate Paracetamol-Induced Hepatotoxicity in Rats

Background: Herbal medicines have historically been crucial for enhancing human health. Previous studies have highlighted the antioxidant properties of various parts of Citrus sinensis. In light of widespread reliance on plant-based remedies, this study focuses on a particular herbal medicine, Citrus sinensis, known for its rich content of vitamin C, pectins, phenolic compounds, and flavonoids. Objective: This research aims to investigate the hepatoprotective potential of the ethanolic extract of Citrus sinensis peel in vivo, particularly focusing on its antioxidant capabilities. Methods: The study utilized biochemical parameters including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), bilirubin, and total proteins to assess the hepatoprotective action of the Citrus sinensis peel extract in serum of Wistar albino rats. The rats were divided into five groups, with varying treatments including a control group, a paracetamol-induced hepatotoxicity group, and groups receiving different doses of the Citrus sinensis extract. Results: Treatment with the ethanolic extract of Citrus sinensis peel at doses of 200 mg/kg and 400 mg/kg significantly mitigated the paracetamol-induced elevation of serum levels of AST, ALT, ALP, bilirubin, and total proteins. These improvements were comparable to those observed with the standard drug, silymarin. Conclusion: The study confirms the hepatoprotective effects of Citrus sinensis peel extract against paracetamol-induced liver damage. This protection was evident both biochemically and histopathologically, suggesting the potential therapeutic utility of Citrus sinensis in liver disorders.

The Hepatoprotective Effect of Omega-7 Against Paracetamol-Induced Hepatotoxicity in Male Rats

Abstract Paracetamol toxicity, whether accidental or not is a worldwide issue that leads to hepatotoxicity, acute liver failure, as well as irreversible liver injury requiring liver transplantation. Omega-7 is a monounsaturated fatty acid with a number of beneficial properties. The aim of the present study was to assess the potential protective role of omega-7 fatty acid against hepatotoxicity induced by paracetamol in male rats. Thirty male Rats were separated into five groups (six rats in each group) and received the following treatment: group 1 received liquid paraffin orally via gavage tube for seven days successively, group 2 received liquid paraffin orally via gavage tube for seven days successively, and on day eight, rats received a single intraperitoneal injection of paracetamol (500 mg/kg/day), group 3 received omega-7 (300 mg/kg/day) orally via gavage tube for seven days successively, group 4 received omega-7 (100 mg/kg/day) orally via gavage tube for seven days successively, and on day eight, rats received a single intraperitoneal injection of paracetamol (500 mg/kg/day), group 5 received omega-7 (300 mg/kg/day) orally via gavage tube for seven days successively, and on day eight, rats received a single intraperitoneal injection of paracetamol (500 mg/kg/day). On day nine, rats have been sacrificed by cervical dislocation and liver homogenate samples were collected for analysis. This study showed that there was a significant decrease in hepatic superoxide dismutase, catalase, glutathione-peroxidase and glutathione levels, accompanied with significant increase in hepatic malondialdehyde level in paracetamol group compared to the negative control group. However, administration of omega-7 resulted in significant increase in hepatic superoxide dismutase, catalase and glutathione levels and significant decrease in hepatic malondialdehyde level compared to paracetamol group. In conclusion, omega-7 has a protective effect on paracetamol-induced hepatotoxicity in rats. Keywords: Antioxidant, Hepatotoxicity, Omega-7, Oxidative stress, Paracetamol.

Assessment of the hepatoprotective effect of Moringa oleifera leaves ex-tract (MOLE) on paracetamol-induced hepatotoxicity in Albino Wistar rats

The current study aimed to investigate the hepatoprotective efficacy of Moringa oleifera (MOLE) against liver damage in male rats caused by paracetamol. Four groups of twenty-four male Wister rats, weighing between 150 and 200 gm each, were created. To cause liver damage, a dose of 2g/kg of paracetamol was given once a day for a week, and a dose of 300mg/kg B.W. of MOLE was given orally via gavage for four weeks. As an example hepatoprotective medication, silymarin was administered orally at a rate of 100 mg/kg body weight. Enzyme levels in the liver including total bilirubin, ALT, AST, and ALP were utilized to gauge the extent of recovery after hepatic damage. As antioxidant enzymes, SOD and CAT were evaluated. In male rats, paracetamol-induced liver damage was successfully avoided by silymarin and MOLE. The hepatoprotective effects of the extract were evidenced by a noteworthy reduction in the levels of blood enzymes include TB, ALT, AST, and ALP, along with a decline in tumour necrosis factor alpha (TNF-α). Additionally, there was a rise in the levels of antioxidant enzymes SOD and CAT, as well as interleukin 6 (IL-6).

"Insights From a Rat Model of Paracetamol-Induced Hepatotoxicity into the Molecular Mechanisms of Silymarin and Resveratrol Combination Therapy for Protecting Liver Function"

"Insights From a Rat Model of Paracetamol-Induced Hepatotoxicity into the Molecular Mechanisms of Silymarin and Resveratrol Combination Therapy for Protecting Liver Function"

Antioxidative and Anti-Inflammatory Protective Effects of Fucoxanthin against Paracetamol-Induced Hepatotoxicity in Rats.

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.

Antioxidant and Biological Activities of Mahajanaka Mango Pulp Extract in Murine Models

Mahajanaka mango, a hybrid cultivar of Mangifera indica Linn., is a highly nutritional fruit that is popularly consumed in Thailand. It has been used in traditional medicine due to its abundance of phytonutrients. The present study aimed to investigate the chemical compositions and antioxidant activity of Mahajanaka mango pulp extract (MPE) in vitro. Additionally, we examined its biological activities, including the analgesic, anti-inflammatory, gastroprotective, and hepatoprotective effects of MPE, in murine models. MPE exhibited high levels of phenolic compounds, mangiferin, β-carotene, and vitamin C, and it potentially showed antioxidant properties in an ABTS scavenging assay. The animal results have revealed that oral administration of MPE (1000 mg/kg body weight (BW)) significantly decreased acetic acid-induced writhing responses in mice. Interestingly, local applications of MPE at 1 mg/ear ameliorated ethyl phenylpropiolate (EPP)-induced ear edema, while gavage of MPE at 1000 mg/kg BW significantly decreased carrageenan-induced hind paw edema in rats. MPE can also protect against gastric ulcers induced by stress, hydrochloric acid/ethanol, and indomethacin in rats. Indeed, MPE (250 mg/kg BW) markedly lowered the level of serum alanine aminotransferase activity and hepatic lipid accumulation in rats with CCl4- and paracetamol-induced hepatotoxicity. Taken together, the findings suggested that MPE exerts potent antioxidant, analgesic, anti-inflammatory, gastroprotective, and hepatoprotective effects.

MICROENCAPSULATION OF SCHLEICHERA OLEOSA L. LEAF EXTRACT IN MAINTAINING THEIR BIOLOGICAL ACTIVITY: ANTIOXIDANT AND HEPATOPROTECTIVE

Objective: Schleichera oleosa L. leaf extract has been studied to have antioxidant activity due to the presence of phenolic compounds, especially flavonoids. Flavonoid compounds that have potential as antioxidants are generally unstable and rapidly degraded due to the influence of moisture, heat, light, oxygen, and other reactive components. Microencapsulation is an effective method for maintaining the stability of bioactive compounds. This study aims to formulate S. oleosa leaf extract microcapsules and test their stability based on the results of physical characterization, antioxidant, and hepatoprotective activities. Methods: The microencapsulation process of S. oleosa leaf extract was carried out using a fluid bed coating using a polyvinyl alcohol matrix and Ethocel 10 cP. Stability test using a climatic chamber at 40 °C for 90 d. Physical characteristics consist of drying shrinkage, flow rate, angle of repose, compressibility, particle size, and scanning electron microscope (SEM) picture. Antioxidant activity was tested in vitro using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method, and hepatoprotective activity was tested using the paracetamol-induced hepatotoxicity method in rats. Results: The results showed that the microcapsules, after stability testing, could maintain the total phenolic content and antioxidant activity in the strong category with IC50 values ranging from 50 to 100 ppm. The results of the hepatoprotective activity test of S. oleosa leaf extract microcapsules tested on days 0 and 90 (after stability testing) could significantly reduce SGOT and SGPT levels compared to negative controls after being induced with paracetamol. Still, this effect was lower than that of curcumin, which is known to be hepatoprotective. Conclusion: The application of the microencapsulation method to S. oleosa leaf extract plays an essential role in maintaining physical stability and maintaining its biological activity as an antioxidant and hepatoprotector.

Isolation, characterization, structural elucidation and in vivo hepatoprotective studies of phytoconstituents obtained from the fruits of <i>Cordia obliqua</i> Willd

Purpose: To isolate, characterize, and investigate the hepatoprotective effect of phyto-constituents from fruits of Cordia obliqua Wild in paracetamol-induced hepatotoxicity in Wistar rats.
 Methods: Ethanol and aqueous extracts of C. obliqua fruits were screened for phytochemicals. The extracts were subjected to column chromatography and preparative thin-layer chromatography (TLC) to isolate four novel compounds. Compounds were characterized using infrared spectroscopy (IR), mass spectroscopy (MS), as well as 1H and 13C nuclear magnetic resonance (NMR). The isolated compounds were assessed for acute toxicity, in vivo hepatoprotective and antioxidant potential (dose: 5 mg/kg) in paracetamol-induced (75 mg/kg) hepatotoxicity through oral route in Wistar rats.
 Results: Phytochemical analysis of ethanol (COE) indicated the presence of fatty acids, anthraquinones, glycosides, saponins, alkaloids, tannins, flavonoids, coumarins, phenolics, triterpenes, and sterols. Compounds A, B, and C were identified from COE. Treatment at 50 mg/kg significantly reduced aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGTP), and total bilirubin (TB), as well as increased total protein and total alkalinity levels in serum compared to the positive control. Liver histo-architecture showed improvements compared to the positive control, indicating hepatic protection.
 Conclusion: The isolated compounds (A, B and C) from COE exhibit hepatoprotective effects attributed to flavonoids and phenolics with free radical scavenging properties. Further research is needed to identify key mechanisms responsible for hepatoprotective effects.

Olive and Turmeric Oils: Nutraceutical Effectiveness against Paracetamol-Induced Hepatotoxicity in Experimental Rats

Olive and Turmeric Oils: Nutraceutical Effectiveness against Paracetamol-Induced Hepatotoxicity in Experimental Rats

Restorative effects of Silymarin milk thistle on the liver following paracetamol-induced hepatotoxicity in adult albino rats

Background: Paracetamol-induced hepatotoxicity has been on the rise worldwide and there is a need for restorative measures to counter its effect. Silymarin milk thistle is an herb that has been used for the treatment of liver conditions. This current study aimed at determining the restorative effects of silymarin milk thistle on the liver morphology and terminal body weight of paracetamol-induced hepatotoxicity among albino rats.
 Methodology: This study was conducted at Maseno University, and a posttest-only experimental design was used. A total of 24 adult albino rats were randomly selected and grouped into four groups, each consisting of six albino rats. Positive control received (5 days of high-dose paracetamol 750mg/kbwt) and negative control received no drug intervention. Three experimental groups received high-dose paracetamol for five days and were thereafter given varying doses of silymarin milk thistle (low- dose group: 200 mg/kbwt, medium-dose: 400 mg/kbwt and high-dose: 600 mg/kbwt) of silymarin milk thistle. Gross liver morphological data and body weight were expressed as mean ± SEM. A one-way ANOVA analysis of variance was used to test the mean groups and a post hoc test was used to test the difference between the mean groups. A p ≤ 0.05 was found to have statistical significance at a 95% confidence interval.
 Results: This current study found that there was a significant (p≤ 0.0001) increase in mean weight, volume, length, and width of the liver in the high dose silymarin milk thistle group as compared to the positive control group. There was a significant (p≤ 0.0001) reduction in the terminal mean body weight of the rats in the positive control group, low dose silymarin group and the medium dose silymarin group respectively, as compared to the negative control group.
 Conclusion: Silymarin milk thistle was found to have restorative effects on the liver morphology and body weight following paracetamol toxicity at high dose.

Đánh giá tác dụng chống oxy hóa và bảo vệ gan trên thực nghiệm của cây muồng lùn

Antioxidant and hepatoprotective effects of different fractions of extract from Chamaecrista pumila (Lam.) K. Larsen were investigated by employing in vitro and in vivo models, respectively. In vitro antioxidant activity of ethanol extract and its n-hexan, ethyl acetate, chloroform, n-butanol and remained water fraction extracts obtained from C. pumila was assessed by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and superoxide radical scavenging assay. In vitro results revealed that the ethanol extract had potential DPPH radical and superoxide radical scavenging activities with an IC50 value of 18.65 (9.91-35.08) µg/ml and 12.33 (5.24-29.02) µg/mL, respectively. Among fractions extracted from ethanol extract, the ethyl acetate fraction possessed highest antioxidant property through DPPH radical scarvenging activity with an IC50value of 9.98 (6.23-16.01) µg/mL and superoxide radical scavenging activity with an IC50 value of 8.38 (6.11-11.50) µg/mL. In vivo hepatoprotective activities of ethanolic extract and ethyl acetate fraction obtained from C. pumila were investigated in mice using a model of paracetamol-induced hepatotoxicity. Ethanol extract of C. pumila at doses of 250 mg/kg and 500 mg/kg decreased levels of serum transaminases ASAT. Ethyl acetate fraction of C. pumila at doses of 250 mg/kg and 500 mg/kg significantly improved the parameters of paracetamol-induced liver injury including ASAT, ALAT and superoxide dismutase (SOD) activities; ethyl acetat fraction of C. pumila at dose of 500 mg/kg also exhibited in vivo antioxidant properties by reducing malondialdehyde (MDA) content and increasing glutathione (GSH) content.

A Comparative GC/MS Analysis of Citrus Essential Oils: Unveiling the Potential Benefits of Herb-Drug Interactions in Preventing Paracetamol-Induced Hepatotoxicity.

Our study aimed to test the potential of Citrus oils in protecting against paracetamol (PAR)-induced hepatotoxicity. The essential oils of Pineapple sweet orange (OO), Murcott mandarin (MO), Red grapefruit (GO), and Oval kumquat (KO) were investigated using gas chromatography coupled with mass spectrometry (GC/MS). Twenty-seven compounds were identified, with monoterpene hydrocarbons being abundant class. d-Limonene had the highest percentage (92.98 %, 92.82 %, 89.75 %, and 94.46 % in OO, MO, GO, and KO, respectively). Hierarchical cluster analysis (HCA) and principal components analysis (PCA) revealed that octanal, linalool, germacrene D, and d-limonene were the principal discriminatory metabolites that segregated the samples into three distinct clusters. In vitro antioxidant capacities were ranged from 1.2-12.27, 1.79-5.91, and 235.05-585.28 μM Trolox eq/mg oil for 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic (ABTS), ferric-reducing antioxidant power (FRAP), and oxygen radical absorbance capacity (ORAC), respectively. In vivo, citrus oils exhibited a significant reduction in alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and nitric oxide (NO). Additionally, there was an increase in glutathione reductase (GSH), and the liver architecture was nearly normal. Molecular docking revealed that d-limonene exhibited a good inhibitory interaction with cytochrome P450 (CYP450) isoforms 1A2, 3A4, and 2E1, with binding energies of -6.17, -4.51, and -5.61 kcal/mol, respectively.

Taming Food-Drug Interaction Risk: Potential Inhibitory Effects of Citrus Juices on Cytochrome Liver Enzymes Can Safeguard the Liver from Overdose Paracetamol-Induced Hepatotoxicity.

Paracetamol overdose is the leading cause of drug-induced hepatotoxicity worldwide. Because of N-acetyl cysteine's limited therapeutic efficacy and safety, searching for alternative therapeutic substitutes is necessary. This study investigated four citrus juices: Citrus sinensis L. Osbeck var. Pineapple (pineapple sweet orange), Citrus reticulata Blanco × Citrus sinensis L. Osbeck (Murcott mandarin), Citrus paradisi Macfadyen var. Ruby Red (red grapefruit), and Fortunella margarita Swingle (oval kumquat) to improve the herbal therapy against paracetamol-induced liver toxicity. UHPLC-QTOF-MS/MS profiling of the investigated samples resulted in the identification of about 40 metabolites belonging to different phytochemical classes. Phenolic compounds were the most abundant, with the total content ranked from 609.18 to 1093.26 μg gallic acid equivalent (GAE)/mL juice. The multivariate data analysis revealed that phloretin 3',5'-di-C-glucoside, narirutin, naringin, hesperidin, 2-O-rhamnosyl-swertisin, fortunellin (acacetin-7-O-neohesperidoside), sinensetin, nobiletin, and tangeretin represented the crucial discriminatory metabolites that segregated the analyzed samples. Nevertheless, the antioxidant activity of the samples was 1135.91-2913.92 μM Trolox eq/mL juice, 718.95-3749.47 μM Trolox eq/mL juice, and 2304.74-4390.32 μM Trolox eq/mL juice, as revealed from 2,2'-azino-bis-3-ethylbenzthiazoline-6-sulfonic acid, ferric-reducing antioxidant power, and oxygen radical absorbance capacity, respectively. The in vivo paracetamol-induced hepatotoxicity model in rats was established and assessed by measuring the levels of hepatic enzymes and antioxidant biomarkers. Interestingly, the concomitant administration of citrus juices with a toxic dose of paracetamol effectively recovered the liver injury, as confirmed by normal sections of hepatocytes. This action could be due to the interactions between the major identified metabolites (hesperidin, hesperetin, phloretin 3',5'-di-C-glucoside, fortunellin, poncirin, nobiletin, apigenin-6,8-digalactoside, 6',7'-dihydroxybergamottin, naringenin, and naringin) and cytochrome P450 isoforms (CYP3A4, CYP2E1, and CYP1A2), as revealed from the molecular docking study. The most promising compounds in the three docking processes were hesperidin, fortunellin, poncirin, and naringin. Finally, a desirable food-drug interaction was achieved in our research to overcome paracetamol overdose-induced hepatotoxicity.

Hepatoprotective and nephroprotective effects of Sedum adenotrichum in paracetamol-induced hepatotoxicity in rabbits.

Sedum adenotrichum (SA) has been traditionally used against various ailments due to the presence of several important phenolic compounds. This study provides a scientific basis for the hepatoprotective and nephroprotective potentials of Sedum adenotrichum in paracetamol-induced toxicity in rabbits. Methanolic extract of Sedum adenotrichum along with paracetamol was administered orally to rabbits alone or in combination with paracetamol for 2weeks. Results showed that paracetamol-induced toxicity was correlated with a significant change in biochemical, hematological parameters, and loss in body weight of rabbits, and the curative effect of SA methanolic extract was found. Liver and kidney histological studies showed significant induced toxicity of paracetamol and correspondence restoration power of SA methanolic extract. The levels of reduced glutathione, radical scavenging activity, and lipid peroxidation in the liver were restored to normal by the methanolic extract of SA. This study confirmed the protective effect of SA methanolic extract against hepatotoxicity and nephrotoxicity caused by paracetamol. Biochemical analysis of the methanolic extract of SA confirmed the presence of bioactive phenolic compounds which have hepatic and nephroprotective potentials.