Cisplatin-induced Hepatotoxicity In Rats Research Articles

Potential therapeutic effect of Thymoquinone on Cisplatin-induced hepatotoxicity in rats

Aim: Cisplatin (CIS), an antineoplastic agent, shows serious side effects such as hepatotoxicity. Thymoquinone (ThQ) is a powerful anti-oxidant with many beneficial effects such as anti-inflammatory, anti-tumoral. The aim of this study was to investigate whether ThQ treatment has hepatoprotective effect in CIS-induced hepatotoxicity model in rats and also to determine how CIS and/or ThQ treatments affect OTULIN levels, one of the deubiquitinases, in liver tissue. Materials and Methods: The 28 rats used in the study control (application not done), CIS (7 mg/kg CIS, first day of experiment, intraperitoneal), CIS+ThQ (7 mg/kg CIS, first day of experiment, intraperitoneal + 10 mg/kg/day ThQ, oral gavage) and ThQ (10 mg/kg/day ThQ, oral gavage) were divided into four equal groups (n=7). The experiment was terminated upon completion of all applications (day 15). The effects of CIS and\or ThQ apps on liver tissues were examined biochemically, histopathologically and immunohistochemically. Results: CIS application increased liver enzyme levels, histopathological changes, inflammation, oxidative stress and apoptosis in liver tissue and caused a decrease in OTULIN level. However, ThQ administration showed a positive regulatory effect on CIS-induced changes in liver tissue. Conclusion: ThQ supplementation has a hepatoprotective effect against CIS-induced liver tissue damage.

Curative Effect of AD-MSCs against Cisplatin-Induced Hepatotoxicity in Rats is Potentiated by Azilsartan: Targeting Oxidative Stress, MAPK, and Apoptosis Signaling Pathways.

Despite its clinical value, cisplatin (CISP) is complicated by marked hepatotoxicity via inducing oxidative stress, inflammatory, and apoptotic pathways. This study aims to explore the protective impact of azilsartan (AZIL), an antihypertensive drug, in addition to adipose tissue-derived mesenchymal stem cells (AD-MSCs) on CISP-induced hepatotoxicity. After characterization and labeling of AD-MSCs by PKH26 dye, 54 Wistar male albino rats were randomly divided into nine groups: I (CONT), II (AZIL.H), III (CISP), IV (CISP + AZIL.L), V (CISP + AZIL.H), VI (CISP + AD-MSCs), VII (CISP + AZIL.L + AD-MSCs), VIII (CISP + AZIL.H + AD-MSCs), and IX (CISP + VITA C). Serum alanine aminotransferase (ALT), alanine aminotransferase (AST), and albumin levels were determined. Assessment of reactive oxygen species, malondialdehyde, and glutathione contents, and superoxide dismutase activity and histopathological evaluations were done on hepatic tissue. Quantitative real-time PCR was utilized to estimate the expression of TNF-α and IL-6 genes. Cell homing of labeled AD-MSCs to the liver tissues was investigated. Hepatic expression of JNK1/2, ERK1/2, p38, Bax, Bcl-2, and cleaved caspase-3 proteins was investigated by western blot analysis. CISP elevated serum ALT and AST activities, reduced albumin level, and remarkably changed the hepatic architecture. It increased the expression TNF-α and IL-6 genes, raised the expression of JNK1/2, ERK1/2, p38, Bax, and cleaved caspase-3 proteins, and diminished the Bcl-2 protein. By contrast, treatment of animals with either AZIL or AD-MSCs dramatically reduced the effects of CISP injection. Moreover, treatment with combination therapy (AZIL.L or H + AD-MSCs) considerably mitigated all previously mentioned alterations superior to AZIL or AD-MSCs alone, which might be attributed to the AZIL-enhanced homing ability of AD-MSCs into the injured liver tissue. In conclusion, the present findings demonstrated that AZIL improves the hepatoprotective potential of AD-MSCs against CISP-induced hepatotoxicity by modulating oxidative stress, mitogen-activated protein kinase, and apoptotic pathways.

Hepatoprotective effects of Alpinia officinarum rhizome extract on cisplatin-induced hepatotoxicity in rats: A biochemical, histopathological and immunohistochemical study

BackgroundAlpinia officinarum is a member of the ginger family (Zingiberaceae), which is widely cultivated in Asia and traditionally used for its anti-inflammatory, antimicrobial, and antihyperlipidemic qualities. This study aimed to evaluate the effect of Alpinia officinarum rhizome extract (AORE) on cisplatin (CP)-induced hepatotoxicity in rats. MethodsForty-four male rats were divided into six groups including the control group, AORE control group, CP control group, and three groups of CP (7 mg/kg dose, on the 10th day) with AORE (at concentrations of 100, 200 and 400 mg/kg, daily for 14 days). After 14 days, the rats' livers were removed and their liver function was assessed using biochemical marker enzymes including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) activities and albumin, total protein, and total bilirubin (T. bilirubin). Oxidative stress was assessed by evaluating malondialdehyde concentration and hepatic superoxide dismutase activity, histopathological and immunohistochemical tests were also conducted. ResultsResults demonstrated that treatment with AORE reduced the toxicity in levels of the hepatic biomarkers in cp-induced groups. AORE treatment decreased oxidative stress and improved histopathological indexes. Furthermore, immunohistochemical (IHC) investigation showed the B-cell lymphoma 2 (Bcl-2) upsurging and p53 downregulating expression exhibiting the recovery following AORE administration. ConclusionThe founding suggested that AORE administration has positive biochemical, histopathological, and immunohistochemical impacts on the ameliorating of hepatotoxicity in CP-induced rats.

Retinoic Acid Potentiates the Therapeutic Efficiency of Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) against Cisplatin-Induced Hepatotoxicity in Rats

(1) Background: Hepatotoxicity is a common health problem, and oxidative stress plays a crucial role in its underlying mechanisms. We inspected the possible effect of retinoic acid (RA) in the potentiation of hepatoprotective effect of bone marrow mesenchymal stem cells (BM-MSCs) against Cisplatin (Cis)-induced hepatotoxicity. (2) Methods: 60 male Sprague Dawley rats (SD) were separated randomly and designated to six main equal groups as follows: (1) Control group, (2) Cis group (rats got Cis 7 mg/Kg i.p.), (3) Cis + vehicle group (as group 2, but rats received the (vehicle) culture media of BM-MSCs), (4) Cis as in group 2 + BM-MSCs (1x106), (5) Cis as for group 2 + RA 1 mg/Kg i.p., and (6) Cis and BM-MSCs as for group 3 + RA as for group 4. Liver injury was assessed by measuring liver enzymes (ALT, AST), while liver toxicity was evaluated by histopathological examination. Apoptotic marker caspase-3 protein was detected immunohistochemically. Real time PCR was performed to detect NADPH oxidase and TNF-α at transcription levels. Oxidative stress was investigated by colorimetric measurement of MDA, GSH and catalase. (3) Results: Contrary to the Cis group (p < 0.05), BM-MSCs/RA supplementation resulted in a substantial decrease in serum levels of hepatic impairment indicators such as ALT, AST and oxidative stress markers such as MDA, as well as an increase in hepatic GSH, Catalase, and a decrease in expression of TNF-α and downregulation of NADPH oxidase. The improvement after therapy with BM-MSCs/RA was confirmed by histopathological examination. Moreover, the downregulation of caspase-3 in liver tissue after BM-MSCs/RA treatment was validated by immunohistochemistry investigation. (4) Conclusions: BM-MSCs and RA attenuated Cis induced hepatotoxicity through downregulation of oxidative stress resulted in modulation of anti-inflammatory TNF-α and apoptosis caspase-3 indicating a promising role in hepatotoxicity.

Hepatoprotective effect of Betulin against Cisplatin‐induced toxicity via inhibiting apoptotic and Nek7‐independent NLRP3 inflammasome pathways: An in vivo study

Background Despite its wide use, cisplatin induces serious multiorgan toxicity via stimulating vicious inflammatory, oxidative stress and apoptotic cascades. Betulin is a naturally occurring triterpene that has been shown to protect against cisplatin-induced nephrotoxicity, yet its protective effect against cisplatin-induced hepato- and cardiotoxicity has not been studied. Aim of the work Here we investigated the potential protective effect of betulin against cisplatin-induced hepatotoxicity in rats and the potential underlying mechanism of this effect. Methods Induction of cisplatin acute hepatotoxicity was achieved by single intraperitoneal injection of 10 mg/kg in the middle of the experimental model timeframe. Betulin treatment (8 mg/kg) was intraperitoneally injected daily for total period of 10 days. Results Treatment with betulin significantly improved biochemical liver functions as indicated by restoring cisplatin disrupted levels of serum Aspartate transaminase (AST), Alanine transaminase (ALT), albumin and total bilirubin. In addition, betulin significantly improved histopathological structural features of liver tissues and significantly reduced hepatic tissue fibrosis turnover. Betulin hepatoprotective effect was mediated via reducing cisplatin-provoked oxidative stress, inflammation and apoptosis. Specifically, betulin increased hepatic total antioxidant capacity and decreased hepatic malondialdehyde levels compared to cisplatin group. In addition, betulin significantly attenuated cisplatin-induced NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome pathway activation as evident by downregulating hepatic tissue levels of NLRP3, caspase-1 and interleukin-1β (IL-1β). Interestingly, despite of the cisplatin-induced upregulation of the hepatic NLRP3 interacting protein, mitotic kinase NIMA-related kinase 7 (Nek7), betulin did not induce any significant alteration of its levels in liver tissues. Betulin significantly reduced cisplatin-induced apoptosis induction as indicated by significant reduction of the apoptotic proteins P53 and Bax, significant reduction of caspases-8, -9 and -3 and upregulation of the anti-apoptotic protein Bcl2. Conclusion To the best of our knowledge, this is the first study to address the hepatoprotective effect of betulin against cisplatin-induced liver injury through modulation of inflammatory and apoptotic pathways.

Epigallocatechin gallate and coenzyme Q10 attenuate cisplatin-induced hepatotoxicity in rats via targeting mitochondrial stress and apoptosis.

Despite the extensive use of cisplatin (CP) as a chemotherapeutic agent, its clinical use is often restricted by undesirable side effects, such as toxicity to normal tissues. The aim of this study was to probe the effect of a combinatorial treatment of low multiple doses of antioxidants on CP-induced toxicity and the mitochondrial apoptotic pathway in hepatocytes. Animals received a single toxic dose of CP (7.5 mg/kg body weight) with or without combined multiple doses of epigallocatechin gallate (EGCG) and coenzyme Q10 (CoQ10) (15 and 5 mg/kg body weight, respectively). CP-treated animals showed altered biochemical parameters, denoting hepatotoxicity, which was markedly improved by the multidose treatment with EGCG + CoQ10. The increased levels of oxidants found in the cytosolic and mitochondrial fractions isolated from the liver of CP-administered rats were significantly attenuated by the combinatorial doses of antioxidants. EGCG + CoQ10 ameliorated the CP-induced compromised antioxidant defenses, oxidative modification of macromolecules, decreased activities of respiratory chain enzymes, altered membrane depolarization, and swelling of liver mitochondria. Furthermore, EGCG + CoQ10 treatment inhibited CP-induced apoptosis by suppressing the activation and mitochondrial accumulation of proapoptotic proteins and preventing the inhibition of antiapoptotic protein expression, cytochrome c efflux, caspase-3 activation, and DNA fragmentation. Histological findings further confirmed the protective effects of EGCG + CoQ10 against CP-induced cellular injury. Our findings revealed that the combination of EGCG and CoQ10, owing to their individual antioxidant properties, can be an effective remedy, which by maintaining redox hemostasis attenuate the mitochondrial stress-mediated molecular and cellular processes involved in CP-induced liver toxicity and cell death.

Protective Effect of Combination Commercial Black Seed Oil (Nigella sativa) and Honey Against Cisplatin-Induced Hepatotoxicity in Rats

Background: The chemotherapeutic use of cisplatin (CP) is restricted because of its hepatotoxicity induced by oxidative stress. Malondialdehyde (MDA) is a secondary product of lipid peroxidation as a biomarker of oxidative stress. Individual administration of black seed oil (BSO) or honey (H) demonstrated hepatoprotective effect in rats. Interaction of both substances when administrated as combination can be evaluated using combination index (CI) to quantitatively depict synergism (CI<1), additive (CI=1) and antagonism effect (CI>1). Objective: to know the combination effect of BSO and honey on rat liver tissue given CP exposure. Methods: This study used 30 rats were divided into 10 groups. Normal group (N); Negative control group (NC); P1-P4 groups were administerated BSO (1 and 2 mL/kg) and honey (3.7 and 7.4 mL/kg); P5-P8 groups were combination of BSO and H. P1-P8 groups were given BSO and honey orally for 21 days. On the 18th day, NC and P1-P8 groups were given CP 8 mg/kg intraperitoneally, while the N group was given NaCl 0.9% 1 mL/kg intraperitoneally. Result: Malondialdehyde (MDA) levels were found to be lower in P1-P8 groups compared to negative control group and P6 and P7 groups have levels equivalent to MDA levels of normal control group (p > 0.05). Conclusion: Combination of BSO and honey provides a protective effect on cisplatin-induced rat liver tissue damage indicated by reduced MDA levels, but all combination group showed antagonism effect.

Protective Effect of Combination Commercial Black Seed Oil (Nigella sativa) and Honey Against Cisplatin-Induced Hepatotoxicity in Rats

Background: The chemotherapeutic use of cisplatin (CP) is restricted because of its hepatotoxicity induced by oxidative stress. Malondialdehyde (MDA) is a secondary product of lipid peroxidation as a biomarker of oxidative stress. Individual administration of black seed oil (BSO) or honey (H) demonstrated hepatoprotective effect in rats. Interaction of both substances when administrated as combination can be evaluated using combination index (CI) to quantitatively depict synergism (CI<1), additive (CI=1) and antagonism effect (CI>1). Objective: to know the combination effect of BSO and honey on rat liver tissue given CP exposure. Methods: This study used 30 rats were divided into 10 groups. Normal group (N); Negative control group (NC); P1-P4 groups were administerated BSO (1 and 2 mL/kg) and honey (3.7 and 7.4 mL/kg); P5-P8 groups were combination of BSO and H. P1-P8 groups were given BSO and honey orally for 21 days. On the 18th day, NC and P1-P8 groups were given CP 8 mg/kg intraperitoneally, while the N group was given NaCl 0.9% 1 mL/kg intraperitoneally. Result: Malondialdehyde (MDA) levels were found to be lower in P1-P8 groups compared to negative control group and P6 and P7 groups have levels equivalent to MDA levels of normal control group (p > 0.05). Conclusion: Combination of BSO and honey provides a protective effect on cisplatin-induced rat liver tissue damage indicated by reduced MDA levels, but all combination group showed antagonism effect.

Preventive Effects of Polygonum minus Essential Oil on Cisplatin-Induced Hepatotoxicity in Sprague Dawley Rats

Cisplatin is a chemotherapeutic agent widely used in treating various types of cancer. However, its usage is restricted due to the adverse hepatoxicity, as seen in approximately 36% of cancer patients receiving cisplatin treatment. Polygonum minus essential oil has high antioxidant capacity, and is enriched with terpenoids and phenolic compounds. The objective of this study was to investigate effects of P. minus essential oil (PmEO) supplementation on cisplatin-induced hepatotoxicity in rats. Male rats were divided into seven different groups, namely: control (C), cisplatin-induced (CP), positive control with β-caryophyllene 150 mg/kg (BCP), PmEO 100 mg/kg (PmEO100CP), PmEO 200 mg/kg (PmEO200CP), PmEO 400 mg/kg (PmEO400CP) and PmEO 400 mg/kg alone (PmEO400). PmEO and BCP was given orally for 14 days prior to a single dose cisplatin (10 mg/kg) injection on day 15 and rats were sacrificed on day 18. Liver enzymes, histology, ultrastructural morphology and oxidative stress markers such as glutathione, glutathione peroxidase, catalase, superoxide dismutase and malondialdehyde were assayed. Compared to controls, levels of transaminase enzymes, serum bilirubin and oxidative stress were all increased in CP, PmEO200CP and PmEO400CP groups. However, only PmEO100CP and BCP groups reduced these increases in level of transaminase enzymes and oxidative stress compared to CP group. On both light microscopic and ultrastructural examination, CP and PmEO400CP groups showed hepatotoxicity, exhibited by cytoplasmic vacuolation, congested blood sinusoids and increased number of Kupffer cells. However, these changes were minimized in the PmEO100CP group. Therefore, we concluded that PmEO given at 100 mg/kg has preventive effect against cisplatin-induced hepatotoxicity in rats.

Nanoparticles Ellagic Acid Protects Against Cisplatin-induced Hepatotoxicity in Rats Without Inhibiting its Cytotoxic Activity

Nanoparticles Ellagic Acid Protects Against Cisplatin-induced Hepatotoxicity in Rats Without Inhibiting its Cytotoxic Activity

Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity

Hesperidin, a naturally occurring flavonoid, exerts many clinically appreciable effects such as anti-oxidant, anti-allergic and anti-inflammatory actions. The present study aimed to investigate the possible protective effects of multiple doses of hesperidin against cisplatin-induced acute hepatotoxicity in rats. Hesperidin (100 or 200mg/kg po) was given to rats one day before cisplatin (7.5mg/kg, ip) injection. All animals were sacrificed 5 days after cisplatin injection and blood samples were collected for determination of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, triglycerides (TG) and total cholesterol levels. Liver samples were used for the determination of malondialdehyde (MDA), glutathione (GSH), total nitrate and nitrite contents. Western blot analysis was used for the assessment of NF-κB and p-Akt expression and histopathological examination was also performed. Results showed that hesperidin significantly reduced cisplatin-induced elevations in serum ALT and AST activities, TG and total cholesterol levels. It also reduced cisplatin-induced oxidative stress by significant reduction in liver MDA and NO content and elevation of GSH content. In addition, hesperidin significantly counteracted cisplatin-induced increased NF-κB expression and decreased p-Akt expression. Histopathological examination revealed that hesperidin greatly protected liver against cisplatin-induced injury. Moreover hesperidin did not inhibit the cytotoxic effect of cisplatin on cancer cells as determined by MTT assay. Hesperidin decreased cisplatin-induced functional and histopathological liver damage in a dose-dependent manner without affecting its potential cytotoxic effect.

Ameliorative effect of trimetazidine on cisplatin-induced hepatotoxicity in rats.

This study was designed to evaluate the protective effects of trimetazidine (TMZ) against cisplatin (CP) induced liver damage in rats. Animals were distributed among 4 groups as follows: control group; TMZ group (20 mg/kg body mass, per oral), which was treated for 10 days; CP group (6 mg/kg, by intraperitoneal injection), which received a single injection; and the CP + TMZ group (20 mg/kg, per oral), which received TMZ 4 days before and 6 days after CP injection. The extent of hepatic damage was studied by assessing biochemical parameters and histopathological evaluation of the extracted liver tissue. The results revealed that liver enzymes were markedly elevated after injection of CP, as evident from significant increases in the serum levels of alanine transaminase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (γ-GT), and lactate dehydrogenase (LDH), as well as marked changes to the liver architecture, with a significant decrease in serum levels of albumin. There were also marked changes to the antioxidant defense system, as indicated by significant decreases in total antioxidants and hepatic levels of reduced glutathione (GSH) and superoxide dismutase (SOD), together with a significant increase in lipid peroxidation. However, there was a significant increase in the activity of hepatic nuclear factor kappa B (NF-κB) as well as hepatic Bax protein expression. We conclude that TMZ protects against CP-induced liver damage through scavenging free radicals and anti-inflammatory and antiapoptotic effects, as well as through reducing NF-κB activation.

Protective effects of remote ischemic preconditioning against cisplatin-induced hepatotoxicity in rats

Background As cisplatin (CP) remains one of the most effective antineoplastics used in chemotherapy, strategies to protect tissues against CP toxicity are of clinical interest. A major dose-limiting side effect in CP-based chemotherapy is hepatotoxicity. Remote ischemic preconditioning (rIP) represents a noninvasive model for organ protection. The present study was designed to examine, in vivo, the CP-induced hepatic injury and to find the protective probability of rIP in this model in relation to an inflammatory mechanism and the hepatic energetic activity. Materials and methods Twenty-four adult male albino rats were divided equally into three groups that were treated as follows: (i) control group, (ii) CP group (single intraperitoneal injection of CP 7 mg/kg body weight), and (iii) preconditioned group. rIP was induced with three 10-min ischemia/10-min reperfusion cycles of the right hind limbs just before CP injection. The animals were killed 14 days after the treatment. Among all groups, the gene expression of nuclear factor 0κB (NF-κB), coenzyme Q10 (Mito.Q10), an autophagy marker LC3 and fatty acid-binding protein L-FABP was assessed by real-time reverse transcription-PCR in the rat liver tissue, in addition, the serum levels of liver enzymes alanine aminotransferase and aspartate transaminase were measured. Results CP induced an increase in hepatic NF-κB and mitochondrial dysfunction as reflected by the decrease in Mito.Q10 and a significant reduction in the mitochondrial clearance mechanism: mitochondrial autophagy, which is known as mitophagy. Further, CP significantly decreased the expression of the main protein involved in fatty acid transport, L-FABP, which is also considered an effective endogenous antioxidant. However, these alterations were ameliorated in preconditioned rats. Conclusion We can assume that the alleviative outcome of rIP in CP-induced hepatotoxicity could be because of induction of anti-inflammatory and antioxidant responses associated with the upregulation of mitochondrial function.

Sorghum [Sorghum bicolor (L.) Moench] leaf sheath dye protects against cisplatin-induced hepatotoxicity and oxidative stress in rats.

This study sought to determine the protective effect of dietary inclusion of sorghum leaf sheath dye on cisplatin-induced hepatotoxicity and oxidative stress in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups I and II were fed a basal diet, while groups III and IV were fed diets containing 0.5% and 1% sorghum leaf sheath dye, respectively, for 20 days before cisplatin administration. Hepatotoxicity was induced by a single dose of cisplatin (7 mg/kg body weight, i.p.), and the experiment was terminated at 3 days after cisplatin injection. The liver and plasma were studied for hepatotoxicity and antioxidant capacity. Cisplatin caused a significant (P<.05) alteration in plasma and liver enzymatic (catalase, glutathione-S-transferase [GST], and superoxide dismutase [SOD]) and nonenzymatic (glutathione [GSH] and vitamin C) antioxidant indices with a concomitant increase in the malondialdehyde (MDA) content; however, there was a significant (P<.05) restoration of the antioxidant status coupled with a significant (P<.05) decrease in the tissue MDA content, after consumption of diets containing sorghum leaf sheath dye. Furthermore, dietary inclusion of sorghum leaf sheath dye caused a marked reduction in the activities of alanine aminotransferase and aspartate aminotransferase after cisplatin administration. However, the ability of the dye to prevent significant cisplatin-induced alteration of both plasma and liver antioxidant indices suggests an antioxidant mechanism of action. Hence, this protective effect of Sorghum bicolor leaf sheath dye against cisplatin-induced hepatotoxicity in rats reflects its potential and beneficial role in the prevention of liver damage associated with cisplatin administration.

Effect of different doses of propofol on cisplatin-induced hepatotoxicity in rats

Objective To investigate the effect of different doses of propofol on cisplatin-induced hepatotoxicity in rats.Methods Eighty male SD rats weighing 200-250 g,aged 3 months,were randomly divided into 8 groups (n =10 each) ∶ control group (group C),cisplatin 7.5 mg/kg group (group Cis),propofol 180 mg/kg group (group P),intralipid 15 ml/kg group (group Ⅰ),cisplatin 7.5 mg/kg + intralipid 15 ml/kg group (group CisI),cisplatin 7.5 mg/kg + propofol 60 mg/kg group (group CisP1),cisplatin 7.5 mg/kg + propofol 120 mg/kg group (group CisP2),and cisplatin 7.5 mg/kg + propofol 180 mg/kg group (group CisP3).The rats in groups C,Cis,P and I received single intraperitoneal injection of normal saline,cisplatin,propofol and intralipid respectively.While in the groups CisI,CisP1,CisP2 and CisP3,rats received a single intraperitoneal injection of propofol or intralipid at 1 min before a single intraperitoneal injection of cisplatin.At 24 h after cisplatin injection,venous blood samples were taken from inferior vena cava for measurement of plasma ALT and AST activities.The liver tissues were taken for microscopic examination.Results Compared with group C,plasma ALT and AST activities were significantly increased and pathological injury was aggravated in groups Cis,CisI and CisP1-3 (P ＜ 0.05).The activities of ALT and AST were gradually decreased and the pathologic injury was attenuated in groups Cis and CisP1-3 (P ＜ 0.05).Conclusion Propofol can reduce cisplatin-induced hepatotoxicity in a dose-dependent manner in rats. Key words: Propofol ; Cisplatin ; Hepatotoxicity

Effects of Grape seed Extract and Origanum Onites Essential Oil on Cisplatin-Induced Hepatotoxicity in Rats

Cisplatin is a widely used anticancer drug but, it can produce undesirable effects such as hepatotoxicity even in therapeutic doses. The underlying mechanism in hepatotoxicity has been attributed to free oxygen radicals. The present study was de- signed to determine the possible protective effects of grape seed extract (GSE) and Origanum onites essential oil (OOEO) on liver toxicity induced by cisplatin. Ninetysix-male Wistar albino rats were divided into eight groups, twelve in each (Cont- rol, GSE, OOEO, GSE+OOEO, Cisplatin, GSE+ Cisplatin, OOEO+ Cisplatin, GSE+OOEO+ Cisplatin) and followed up for 10 days. Cisplatin and OOEO were injected intraperitoneally. GSE was administered with gavage. The histopathological exami- nation of liver tissues was performed by light microscope. Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) activities and malondialdehyde (MDA) levels were determined in liver tissues. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured in serum. Cisplatin-induced considerable hepatocyte damage under micros- copic examination, and an increase in MDA levels as well as a decrease in the activities of antioxidant enzymes, including SOD, GSH-Px in liver tissues and an increase in serum ALT and AST (p< 0.001). The addition of GSE and/or OOEO signi- ficantly prevented microscopic tissue damage, reversed oxidative stress parameters and biochemical values compared to the cisplatin group (p< 0.001). In conclusion GSE and OOEO may be used in adjuvant therapy to prevent cisplatin-induced hepatotoxicity, but further studies using various doses, different time intervals, and a larger number of animals need to be carried out.

Effects of reduced glutathion and vitamin c on cisplatin-induced hepatotoxicity in rats

Cisplatin (CDDP) is a widely used anticancer drug, however it can produce undesirable side effects such as hepatotoxicity when used at high doses . The aim of the present work to evaluate the protective effect of reduced glutathione (GSH) and vitamin C on CDDP-induced hepatotoxicity . Eighty male Sprague-Dawley rats were divided into eight groups, 10 rats each. Group I , control group. Group II received Cisplatin (7.5 mg /kg, i.p) for 5 consecutive days. Group III received GSH (600 mg/kg /day, i.p). Group IV received vitamin C (250 mg/kg/day, orally) . Group V received GSH for 15 days then CDDP for 5 days. Group VI administered vitamin C for 15 days then CDDP for 5 days. Group VII administered both GSH and CDDP for 5 days . The last Group (VIII) administered both vitamin C and CDDP for 5 days. Serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST] activities (markers of hepatotoxicity), antioxidants (superoxide dismutase [SOD], glutathione peroxidase [GSHPx], catalase [CAT], glutathione reductase [GSHR] activities and gene expression, glutathione [GSH] content) and lipid peroxidation products (malondialdehyde, MDA) in rat liver tissue were measured. CDDP hepatotoxicity was manifested by an increase in serum ALT and AST, elevation of MDA as well as a decrease in GSH and the activities and gene expression of antioxidant enzymes (SOD, GSHPx, CAT, GSHR) in liver tissues. Serum ALT, AST and hepatic MDA decreased in the combination groups in comparison with the CDDP group. The activities and gene expression of SOD, GSHPx, CAT and GSHR and the GSH concentration increased in the combination groups as compared to the CDDP group. Reduced glutathione and vitamin C either taken before or concomitant with cisplatin attenuated the CDDP hepatotoxicity. Key words : GSH , Vitamin C, CDP, Hepatotoxicity.