chrysin and Chemical-and-Drug-Induced-Liver-Injury

Chrysin (CH) is one of the important natural flavonoids with antioxidant and anti-inflammatory activity. The aim of this study was to assess the protective effects of CH on biochemical indexes and histopathological changes in the liver of male Wistar rats exposed to chlorpyrifos (CPF).. We induced sub-chronic toxicity in rats using CPF (10 mg/kg/day, orally) and administrated CH at 12.5, 25, and 50 mg/kg/day for 45 days.. In this study, CPF increased liver enzyme activities compared with the control group (p < 0.05), and co-treated CH with CPF reduced them compared with the non-treated CPF group (p < 0.05). A significant reduction in the liver GSH concentration along with a significant elevation in the concentrations of MDA and NO in the CPF group was observed compared with the control group (p < 0.001). However, CH at a dose of 50 mg could reverse them nearly to the control group (p < 0.001). In the CPF, CPF + CH1, and CPF + CH2 groups, a marked (p < 0.05) increase was found in the serum concentration of IL-6 compared with the control animals. No significant changes were found in the IL-6 concentration of the CPF + CH3 compared with the controls. Moreover, the coadministration of CH plus CPF induced histopathological alterations in liver.. These results suggest that CH attenuates hepatic enzymes and histopathological alterations induced by CPF via modulating oxidative stress and inflammatory indices in rats.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Chlorpyrifos; Flavonoids; Insecticides; Interleukin-6; Liver; Male; Oxidative Stress; Rats; Rats, Wistar

Diclofenac (DF) is a non-steroidal anti-inflammatory drug (NSAID) generally prescribed for the treatment of pain. In spite of the widespread use of DF, hepatotoxicity has been reported after its administration. The current study discloses new evidence as regards of the curative effects of chrysin (CHR) on DF-induced hepatotoxicity by regulating oxidative stress, apoptosis, autophagy, and endoplasmic reticulum (ER) stress.. The animals were separated into five different groups. Group-I was in control. Group-II received CHR-only (50 mg/kg bw, p.o.) on all 5 days. Group-III received DF-only (50 mg/kg bw, i.p.) on 4th and 5th day. Group-IV received DF (50 mg/kg bw) + CHR (25 mg/kg, bw) and group-V received DF (50 mg/kg, bw) + CHR (50 mg/kg, bw) for 5 days.. DF injection was associated with increased MDA while reduced GSH level, activities of superoxide dismutase, glutathione peroxidase, and catalase and mRNA levels of HO-1 and Nrf2 in the liver. DF injection caused apoptosis and autophagy in the liver by up-regulating caspase-3, Bax, LC3A, and LC3B levels and down-regulating Bcl-2. DF also caused ER stress by increasing mRNA transcript levels of ATF-6, IRE1, PERK, and GRP78. Additionally, it was observed that DF administration up-regulated MMP2 and MMP9. However, treatment with CHR at a dose of 25 and 50 mg/kg considerably ameliorated oxidative stress, apoptosis, autophagy, and ER stress in liver tissue.. Overall, the data of this study indicate that liver damage associated with DF toxicity could be ameliorated by CHR administration.

Topics: Animals; Apoptosis; Autophagy; Chemical and Drug Induced Liver Injury; Diclofenac; Endoplasmic Reticulum Stress; Oxidative Stress; Rats; RNA, Messenger

In the present work, chrysin loaded bilosomes were formulated, characterized and evaluated to enhance the hepatoprotective activity of drug. Accordingly, chrysin loaded bilosomes were prepared by applying the thin film hydration method; also, fractional factorial design was used to optimize the production conditions of nanoformulations. The prepared formulations were subjected to different methods of characterization; then the hepatoprotective activity of the optimized one was evaluated in the CCl4 hepatointoxicated mice model. Optimized chrysin loaded bilosomes showed a spherical shape with a particle size of 232.97 ± 23 nm, the polydispersity index of 0.35 ± 0.01, the zeta potential of -44.5 ± 1.27 mv, the entrapment efficiency of 96.77 ± 0.18%, the drug loading % of 6.46 ± 0.01 and the release efficiency of 42.25 ± 1.04 during 48 h. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical-scavenging assay demonstrated the superiority of the anti-oxidant potential of chrysin loaded bilosomes, as compared to pure chrysin. This was in agreement with histopathological investigations, showing significant improvement in serum hepatic biomarkers of CCl4 intoxicated mice treated with chrysin loaded bilosomes, as compared with free chrysin. These results, thus, showed the potential use of bilosomes to enhance the hepatoprotective activity of chrysin via oral administration.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Flavonoids; Liposomes; Mice

Arsenic as a one of the most important toxic metals could induce hepatotoxicity. Previous reports revealed the significance of oxidative stress in promoting of arsenic-induced liver toxicity. The aim of the present investigation is to evaluate the effect of chrysin (CHR), a natural flavonoid with potent antioxidant activity, against sodium arsenite (SA)-induced hepatotoxicity. Thirty male Wistar rats were divided into four groups: Group 1: received normal saline (2 ml/kg/day, orally for 21 days), Group 2: received SA (10 mg/kg/day, orally for 14 days), Group 3, 4 and 5: received CHR (25, 50 and 100 mg/kg/day, respectively, orally for 21 days) and SA (10 mg/kg/day, orally for 14 days) from the 7th day. Serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase were evaluated. Moreover, liver glutathione peroxidase and myeloperoxidase activity as well as levels of protein carbonylation, malondialdehyde, glutathione, catalase, nitric oxide, superoxide dismutase, tumor necrosis factor-α and interleukin-1β were evaluated. Moreover, histological evaluation was done. Our results revealed that treatment with CHR (more potentially at the dose of 100 mg/kg/day) before and alongside with SA significantly mitigated the SA-induced hepatotoxicity. Also, the hepatoprotective effect of CHR was verified by the histological evaluation of the liver. The results of current study demonstrated that CHR (100 mg/kg/day) could mitigate the oxidative stress and inflammation induced by SA in liver tissue.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antioxidants; Arsenites; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Flavonoids; Glutathione; Glutathione Peroxidase; Liver; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Rats; Rats, Wistar; Sodium Compounds; Superoxide Dismutase

Cyclophosphamide (CYP) is a chemotherapeutic agent used in the treatment of autoimmune disorders and malignant diseases. However, its usage is restricted due to its severe side effects, especially hepatotoxicity and nephrotoxicity. This study aimed to investigate the protective role of chrysin (CH) against CYP-induced hepatotoxicity and nephrotoxicity in rats. In the present study, 35 male Wistar rats were randomly divided into 5 groups with each group consisting of 7 rats. The rats were pretreated with CH orally in doses of 25- and 50-mg/kg body weight for 7 consecutive days, and CYP (200-mg/kg body weight, i.p.) was administrated on the 7th day 1 h after the last dose of CH. It was found that CH could ameliorate CYP-induced elevations of ALT, ALP, AST, urea, creatinine, MDA, and hepatorenal deterioration, and enhance antioxidant enzymes' activities such as SOD, CAT, and GPx, and GSH's level. Furthermore, CH reversed the changes in levels of inflammatory, apoptotic, and autophagic parameters such as NF-κB, TNF-α, IL-1β, IL-6, iNOS, COX-2, Bax, Bcl-2, and LC3B in liver and kidney tissues. To conclude, the findings of this study demonstrated that CH has a protective effect against CYP-induced hepatorenal toxicity.

Topics: Acute Kidney Injury; Animals; Apoptosis; Chemical and Drug Induced Liver Injury; Cyclophosphamide; Flavonoids; Inflammation Mediators; Male; Oxidative Stress; Random Allocation; Rats; Rats, Wistar

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Drug-Related Side Effects and Adverse Reactions; Flavonoids; Humans; Rats

Topics: Acetaminophen; Animals; Chemical and Drug Induced Liver Injury; Flavonoids; Rats

Paracetamol (PC) is a widely used analgesic and antipyretic drug, but it leads to acute hepatotoxicity at high doses intakes. This study was aimed to investigate the effects of Chrysin (CR) on hepatotoxicity constituted at high doses of PC in rats. Rats were subjected to oral pretreatment of CR (25 and 50 mg/kg b.w.) via feeding needle for 6 days against hepatotoxicity induced by a single dose of PC (500 mg/kg b.w.) administered orally via feeding needles. Although PC increases lipid peroxidation and liver enzyme activities, it has led to reduction of antioxidant enzyme activities. PC induced inflammatory responses by increasing the levels of TNF-α and IL-1β. Furthermore, PC caused apoptosis and autophagy by increasing activity of Caspase-3 and LC3B level. On the other hand, CR therapy significantly regulated these values in rats. This study demonstrated that CR possesses restorative effect against PC-induced hepatotoxicity by suppressing oxidative stress, inflammation, and apoptotic and autophagic tissue damage.

Topics: Acetaminophen; Administration, Oral; Animals; Antioxidants; Apoptosis; Autophagy; Biomarkers; Chemical and Drug Induced Liver Injury; Cytokines; Enzymes; Flavonoids; Lipid Peroxidation; Liver; Male; Oxidants; Rats, Sprague-Dawley

Trovafloxacin is an antibiotic that was withdrawn from the market relatively soon after its release due to the risk of hepatotoxicity. Trovafloxacin is mainly metabolized to its acyl-glucuronide by uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1. In this study, we examined whether the acyl-glucuronide is involved in the development of hepatotoxicity. A UGT1A1-induced cell model was developed and the toxicity of trovafloxacin acyl-glucuronide was evaluated. The UGT1A1-induced cell model was developed by treating HepG2 cells with chrysin for 48 h. Chemokine (C-X-C motif) ligand 2, a cytokine involved in drug-induced liver injury, was uniquely induced by trovafloxacin in the UGT1A1-induced HepG2 cells. Induction of UGT1A1 resulted in a decrease in cell viability. An in vivo animal study further demonstrated the importance of UGT1A1 in the trovafloxacin-induced liver toxicity. Although the complete mechanism of trovafloxacin-induced liver injury is still unknown, trovafloxacin acyl-glucuronide can be involved in the development of toxic reactions in vitro and in vivo.

Topics: Animals; Chemical and Drug Induced Liver Injury; Chemokine CXCL2; Flavonoids; Fluoroquinolones; Gene Expression Regulation; Glucuronides; Glucuronosyltransferase; Hep G2 Cells; Humans; Mice, Transgenic; Naphthyridines; RNA, Messenger

Intestinal P-glycoprotein (P-gp) and drug-metabolizing enzymes (DMEs) play an important role in the first-pass-metabolism (FPM) and pharmacokinetics (PK) of majority of drugs. Paracetamol is primarily metabolized by conjugation reactions and a little amount (∼15%) undergoes cytochrome P450 (CYP2E1)-mediated oxidative metabolism produces a hepatotoxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). Quercetin and chrysin are naturally occurring flavonoids, reported as modulators of P-gp and DMEs. Therefore, the objective of this study was to evaluate the effects of quercetin and chrysin on the pharmacokinetics of paracetamol using rats and non-everted gut sacs in vitro. Paracetamol was given orally (100 mg/kg) to rats alone and in combination with quercetin (5, 10 and 20 mg/kg) and chrysin (50, 100 and 200 mg/kg) once daily for 21 consecutive days. Blood samples were collected on the 1st day in single dose pharmacokinetic study (SDS) and on the 21st day in multiple pharmacokinetic studies (MDS). The plasma concentrations of paracetamol were determined by HPLC and PK parameters were calculated by using Kinetica (Version 5.1). The maximum plasma concentration (Cmax) and area under the curve (AUC0-12) of paracetamol was significantly increased by quercetin and chrysin co-administration in SDS and MDS. In non-everted rat gut sac method, the absorption of paracetamol was increased by presence of P-gp inhibitors (verapamil, quinidine and ketoconazole), quercetin and chrysin (50 μg/mL). Our findings suggested that the quercetin and chrysin might be inhibited the P-gp and metabolism of paracetamol; thereby increased the systemic exposure of paracetamol. Further studies are needed to evaluate whether the quercetin or chrysin are involved in the formation of NAPQI by CYP2E1 or not on isolated rat hepatocytes or using cell lines.

Topics: Acetaminophen; Administration, Oral; Animals; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B, Member 1; Benzoquinones; Chemical and Drug Induced Liver Injury; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2E1; Dose-Response Relationship, Drug; Drug Interactions; Flavonoids; Imines; Intestinal Absorption; Male; Quercetin; Rats; Rats, Wistar

Methotrexate (MTX), a folic acid antagonist, an effective chemotherapeutic agent is used in the treatment of a wide range of tumors and autoimmune diseases. Moreover, hepatotoxicity limits its clinical use. Several studies have already confirmed that the oxidative stress plays a major role in the pathogenesis of MTX-induced damage in the various organs especially in liver. The aim of this study was to determine the protective effect of Chrysin against MTX-induced hepatic oxidative stress and apoptosis in rats. In the present study, efficacy of Chrysin was investigated against hepatotoxicity caused by MTX in terms of biochemical investigations of antioxidant enzymes, apoptosis, and histopathological alteration in rat liver. In the MTX-treated group there was a significant increase in alanine transaminase, aspartate aminotransferase, lactate dehydrogenase activity and malondialdehyde content as well as decreased glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase activities and reduced glutathione content were also observed compared to the control group as a marker of oxidative stress. Histopathological alterations and apoptosis through the immunopositive staining of p53, cleaved caspases-3 and Bcl-2-associated X protein in rat liver were observed. Pretreatment of Chrysin at both doses prevents the hepatotoxicity by ameliorating oxidative stress, histopathological alterations, and apoptosis and thus our results suggest that Chrysin has a protective effect against hepatotoxicity induced by MTX and it may, therefore, improve the therapeutic index of MTX if co-administration is done.

Topics: Animals; Antioxidants; Apoptosis; bcl-2-Associated X Protein; Biomarkers; Caspase 3; Chemical and Drug Induced Liver Injury; Flavonoids; Glutathione; Immunohistochemistry; Liver; Male; Malondialdehyde; Methotrexate; Oxidative Stress; Rats; Rats, Wistar; Tumor Suppressor Protein p53

Cisplatin is an effective and extensively used chemotherapeutic agent to treat range of malignancies, but its therapeutic use is limited because of dose-dependent nephrotoxicity and hepatotoxicity. Several published reports advocate that supplementation with antioxidant can influence cisplatin induced hepatic damage.. In the present study the Wistar rats were subjected to concurrent prophylactic oral treatment of chrysin (25 and 50mg/kgb.wt.) against the hepatotoxicity induced by intraperitoneal administration of cisplatin (7.5mg/kgb.wt.). Efficacy of chrysin against the hepatotoxicity was evaluated in terms of biochemical estimation of antioxidant enzyme activities, histopathological changes and expression levels of molecular markers of inflammation.. Chrysin ameliorated cisplatin-induced lipid peroxidation, xanthine oxidase activity, glutathione depletion, decrease in antioxidant (catalase, glutathione reductase, superoxide dismutase, glutathione peroxidase and glucose-6 phosphate dehydrogenase) and phase-II detoxifying (glutathione-S-transferase and quinone reductase) enzyme activities. Chrysin also attenuated expression of COX-2, iNOS and levels of NFκB and TNF-α, and hepatic tissue damage which were induced by cisplatin. Histological findings further supported the protective effects of chrysin against cisplatin-induced hepatic damage.. The results of the present study demonstrate that oxidative stress and inflammation are closely associated with cisplatin-induced toxicity and chrysin shows the protective efficacy against cisplatin-induced hepatotoxicity possibly via attenuating the oxidative stress and inflammatory response.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antioxidants; Biomarkers; Chemical and Drug Induced Liver Injury; Cisplatin; Dose-Response Relationship, Drug; Flavonoids; Inflammation; Injections, Intraperitoneal; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar

The objective of current study is to investigate the effects of the administration of chrysin (CH) and quercetin (Q) on rat liver in which oxidative and histological damage had been induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Rats were randomly divided into six equal groups. TCDD was orally administered at the dose of 2 μg/kg/week, and Q and CH were orally administered at the doses of 20 mg/kg day and 50 mg/kg/day, respectively, by gavages dissolved in corn oil. The liver samples to be analyzed for the determination of oxidative and histological alternations were taken from rats at 60 days. The results indicated that although 2,3,7,8-TCDD significantly induced (P ≤ 0.01) lipid peroxidation (increase of MDA levels), it positively affected oxidant/antioxidant system (a decline in the levels of GSH, CAT, GSH-Px, and CuZn-SOD) in rats significantly. The histological changes observed in the liver correlated with the biochemical findings. However, these effects of TCDD on oxidative and histological changes were eliminated by Q and CH treatment. In conclusion, TCDD caused an adverse effect on rat's liver. When Q and CH were given together with TCDD, they prevented hepatotoxicty induced by TCDD. Thus, it is thought that Q and CH may be useful as a new category of anti-TCDD toxicity agent.

Topics: Animals; Antioxidants; Chemical and Drug Induced Liver Injury; Dioxins; Drug Interactions; Environmental Pollutants; Flavonoids; Glutathione; Liver; Male; Polychlorinated Dibenzodioxins; Quercetin; Rats; Rats, Wistar

Chrysin, a natural flavonoid has been reported to possess potent anti-inflammatory, anti-cancer and antioxidation properties. In the present study, we aimed to evaluate the putative protective effect of chrysin, an isoflavone, on carbon tetrachloride (CCl(4))-induced toxicity in male Wistar rats. Intraperitoneal administration of CCl(4) (2 ml/kg) to rats for 4 days resulted in significantly elevated (p < 0.05) serum levels of glutamic oxaloacetic transaminase (SGOT), glutamic pyruvate transaminase (SGPT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH), when compared to normal rats. In addition, the tissues (liver, kidney and brain) and haemolysate samples showed considerable increase in levels (p < 0.05) of malondialdehyde (MDA) and lowered levels (p < 0.05) of reduced glutathione (GSH), vitamin C and E when compared to values in normal rats. Quantitative analysis of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) exhibited lower activities of these antioxidant enzymes in the tissues and haemolysate of CCl(4)-administered rats. The protective action of chrysin on CCl(4)-induced rat was demonstrated with SGPT, SGOT, ALP and LDH resuming to near normal levels, while the mean levels of GSH and of vitamin C and E were elevated, the mean activities of CAT, SOD and Gpx were enhanced and the mean level of MDA was lowered in the tissue and haemolysate samples when compared to the CCl(4)-exposed untreated rats. The expression of the iNOS gene appeared to be up-regulated in the liver and kidney samples of CCl(4)-exposed untreated rats, whereas in CCl(4)-exposed chrysin-treated rats, the mRNA transcript levels of iNOS approximated normal levels. These results strongly suggest that chrysin is able to prevent the oxidative damage induced by CCl(4) in the liver, brain, kidney and haemolysate of male Wistar rats.

Topics: Animals; Antioxidants; Ascorbic Acid; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Disease Models, Animal; Flavonoids; Kidney; Liver; Liver Function Tests; Male; Malondialdehyde; Nitric Oxide Synthase Type II; Oxidoreductases; Rats; Rats, Wistar; RNA, Messenger; Up-Regulation; Vitamin E

Chrysin is a natural, biologically active compound present in many plants and possesses potent anti-inflammatory, anticancer and antioxidation properties. This work was designed to investigate the effect of chrysin, on the hepatoprotective efficacy in d-galactosamine-intoxication rats. d-galactosamine-induced toxicity was manifested by the elevation of serum hepatic marker enzyme activities (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma-glutamyl transpeptidase) and the lipid peroxidation process and by decreasing the antioxidant capacity of the plasma, erythrocyte and tissues. Treatment with chrysin (25, 50 and 100mg/kg body weight) decreased hepatic marker enzyme activities and lipid peroxidation products such as thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes, increased the activities of free-radical scavenging enzymes superoxide dismutase, catalase and glutathione peroxidase and the levels of non-enzymatic antioxidants reduced glutathione, vitamin C and vitamin E. These findings demonstrate that chrysin acts as a hepatoprotective and antioxidant agent against d-galactosamine-induced hepatotoxicity.

Topics: Animals; Antioxidants; Biomarkers; Catalase; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Erythrocytes; Flavonoids; Galactosamine; Glutathione Peroxidase; Kidney; Lipid Peroxidation; Liver; Male; Oxidative Stress; Protective Agents; Random Allocation; Rats; Rats, Wistar; Silymarin; Superoxide Dismutase

Chrysin is a flavonoid that exists in nature and is the major component of some traditional medicinal herbs. We investigated the hepatoprotective and antihyperlipidaemic potential of chrysin against D-galactosamine (a single intraperitoneal injection 400 mg/kg BW) induced hepatotoxicity in male albino Wistar rats. D-GalN rats exhibited an increased hepato and nephro toxicity marker activities aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and gamma glutamyl transpeptidase and total bilirubin level while urea, uric acid and creatinine and lipid profile. It also negatively affected the serum total protein, albumin and A/G ratio. Rats treated with chrysin at different concentrations (25, 50 and 100 mg/kg BW) caused a significant improvement in serum protein level, decreased hepato and nephro toxicity markers. It also decreased the levels of very low density lipoprotein cholesterol and low density lipoprotein cholesterol while high density lipoprotein cholesterol significantly increased. It also decreased the levels of total cholesterol, phospholipids, triglycerides, free fatty acids in the plasma and tissues of liver and kidney. The effect of chrysin (25 mg/kg) is comparable with silymarin, a known hepatoprotective drug. Chrysin thus exhibits hepatoprotective and antihyperlipidaemic activity.

Topics: Animals; Chemical and Drug Induced Liver Injury; Flavonoids; Galactosamine; Liver; Male; Rats; Rats, Wistar