Cisplatin-induced Liver Damage Research Articles

Hepatoprotective Potential of Lycopene in a Rat Model of Cisplatin-Induced Damage: Involvement of Oxidative Cell Damage and Glutathione Metabolism

Application of cisplatin for the treatment of various solid tumors is known to cause liver damage, through an increase in lipid peroxidation and reactive oxygen species production. Lycopene is a powerful antioxidant agent capable of preventing the cells damage, the formation of stronger intercellular bonds and faster cellular metabolism. This study aims to estimate the potential of lycopene in preventing cisplatin induced liver tissue damage by studying the levels of several biochemical parameters (arginase, aminotransferases, alkaline phosphatase, gamma-glutamyl transpeptidase activity, total protein and albumin concentration) reflecting liver function and a panel of liver tissue biomarkers (xanthine oxidase, reduced glutathione, malondialdehyde, protein carbonylated concentration and diamino oxidase activity). These parameters would be studied in male Wistar rats treated with either cisplatin alone or with cisplatin and lycopene. Additionally, microscopic analysis of liver tissue would be conducted as well. Application of the combination of lycopene and cisplatin significantly prevented the disturbance in all here-studied biomarkers of liver tissue damage. Morphological liver tissue alterations followed the changes in hepatic biochemical status. Our results suggest that lycopene could act as a protective agent in cisplatin-induced liver damage in rats.

Ameilorative effect of lycopine against cisplatin toxicity in rats

The following study aimed to investigate the hepato and neuro protective efficacy of Lycopine against Cisplatin which induced hepatotoxicity and neurotoxicity. Twenty Five male Wister rats were used for this experiment they were equally divided into 5 groups (5 rats per group): group (1) served as control group they were injected 1ml saline orally once daily for 20 day, group (2) served as Corn Oil group and they were administrated 1 mL Corn Oil orally once daily for 20 days, group (3) served as Lycopine group and they were administrated (10 mg/kg b.wt) Lycopine orally once daily for 20 days. , group (4) served as Cisplatin treated group and they were injected (6 mg/kg b.wt.) intrapertonialy once at day 10 of experiment and group (5) Lycopine+Cisplatin group and were administrated 10 mg/kg b.wt Lycopine orally once daily for 20 days and injected 6 mg/kg b.wt.) intraperitonialy once at day 10 . Result revealed that Cisplatin induced liver damage indicated by significant increase in liver biomarkers ALP, AlT, AST along with significant decrease in albumin, Moreover marked increase increase in tissue concentrations of malondialdehyde(MDA) and Total antioxidant(TAC) and reduce tissue Glutathione reductase(GSH),that indicated oxidative stress Also results revealed up regulation IL-6 and down regulation IL-10 in liver and brain tissue in compared to control group . However, interestingly concurrent adminsteration of the Lycopine orally at dose level of 10mg/kg b.wt for 20 days with Cisplatin can mitigate these toxic effects caused by Cisplatin.So it is concluded that the antioxidant and the anti-inflammatory effects of Lycopine moderate the Cisplatin-induced hepato and neurotoxicity.

Lycopene prevents cisplatin-induced liver tissue damage, without affecting concentrations of TNF-α or iNOS/NO inflammatory pathway

IntroductionLiver inflammatory response occurring after toxic chemicals injection, such as cisplatin, causes the aggravation in liver damage. Lycopene, a carotenoid, has previously been proven to possess antioxidant, antiinflammatory and antiapoptotic properties. This study objective was to evaluate for the first time the protective effects of lycopene in cisplatin-induced liver damage based on the disturbances in serum and tissue inflammatory parameters. Also, to confirm the extent of changes in inflammation of the studied tissue, a microscopic analysis will be performed.Material and methodsWistar rats were divided into four experimental groups: (I) control; (II) lycopene (2 mg/kg); (III) cisplatin (10 mg/kg) and (IV) lycopene and cisplatin-treated (2 and 10 mg/kg, respectively) animals. After the experiment, we studied changes in serum liver tissue damage associated parameters (ALT, AST, and γ-GT) and liver inflammatory parameters (NO and TNF-α concentrations, myeloperoxidase and iNOS activity, as well as CD68 expression).ResultsApplication of lycopene prevented a rise in evaluated serum parameters induced by cisplatin, while at the same time it did not cause any harmful effect by itself. Lycopene, alone or in combination with cisplatin, decreased the values of all studied liver inflammatory parameters.ConclusionsWe can conclude that lycopene does not prevent liver tissue inflammatory decalin seen after cisplatin application, however, it prevents tissue damage arising from this cytostatic application.

Investigation of the Protective Effects of Caffeic Acid Phenethyl Ester against Cisplatin-induced Liver Damage in Rats

Cisplatin (CP) is used as an effective chemotherapeutic drug in the treatment of various solid tumors. However, side effects such as hepatotoxicity limit the use of the drug. We investigated the protective effects of caffeic acid phenethyl ester (CAPE), one of the active ingredients of propolis, against hepatotoxicity caused by CP treatment in the liver. 38 Wistar albino rats were divided into 4 groups. Control group was given physiological saline solution for 12 day. CP group was given a single dose of CP (7 mg/kg) on the day 7. CP+CAPE group, was given CAPE (10 μmol/kg/day) for 12 days and a single dose of CP (7 mg/kg) on day 7. CAPE group was given CAPE (10 μmol/kg/day for 12 days. Livers of rats sacrificed on the 14th day were stained with hematoxylin-eosin after histological tissue follow-up. The preparations were evaluated histopathologically and scored. Rat weights were measured and recorded at the beginning and end of the experiment. CP caused significant histopathological changes in the liver. CP also prevented the increase in rat weight. CAPE played an effective role as a protective agent against the histopathological changes caused by CP and showed signs of tissue healing. Our results show that CAPE can be protective against hepatotoxicity associated with CP.

The investigation of the effect of fraxin on hepatotoxicity induced by cisplatin in rats.

Objective(s):This study was designed to assess the effect of fraxin which has various biological properties against liver injury induced by cisplatin.Materials and Methods:In our study, 24 Wistar albino rats were randomly assigned to control, fraxin, cisplatin, and fraxin+cisplatin groups. Cisplatin 12 mg/kg IP and fraxin 40 mg/kg orally were applied. When the experiment ended, the rats were sacrificed and the liver tissues were taken rapidly. Liver tissue specimens were maintained under appropriate conditions. Later, biochemical, histopathological, and immunohistochemical evaluations were performed.Results:According to our biochemical findings, oxidant parameters increased while antioxidant parameters decreased in cisplatin group compared with control group. Antioxidant parameters increased but oxidant parameters decreased in fraxin + cisplatin group compared with the cisplatin group. Immunohistochemical evaluations showed that the expressions of TNF-α and Caspase-3 were negative in control and fraxin groups, whereas severe levels were found in the cisplatin group. However, it was determined that the expressions of TNF-α and Caspase-3 were in mild levels in fraxin + cisplatin treatment group. In addition, it was observed that the increase of pathological markers such as coagulation necrosis, hydropic degeneration, dilatation in sinusoid, and hyperemia in the cisplatin group were compatible with our biochemical and immunohistochemical findings. Conclusion:Biochemical, immunohistochemical, and histopathological results revealed that fraxin was effective in relieving cisplatin-induced liver damage.

EFFECT OF6-HYDROXYFLAVONE ONCISPLATININDUCED HISTOPATHOLOGICAL AND BIOCHEMICAL CHANGES IN LIVER OF SPRAGUE-DAWELY RATS

Objective: Chemotherapeutic agents like cisplatin benefits cancer patients by decreasing metastasis, relapse and increase the overall survivability.The clinical effectiveness of these beneficial chemotherapeutics is greatly limited by occurrence of side-effects including hepatotoxicity. Flavonoids possess potent hepatoprotective effects and exhibit antioxidant property. In this study, the hepatoprotective effect of the flavonoid, 6-hydroxyflavone was investigated against cisplatin induced liver damage in rats.
 Materials & Methods: 6-Hydroxyflavone (25 and 50 mg/kg) and silymarin (100 mg/kg)were administered for 14 days and hepatotoxicity was induced by a single injection of cisplatin (7.5 mg/kg) on the 10th day of experiment. The liver tissues were examined for histopathologicalandbiochemical changes. 
 Results: Cisplatin produced histopathological changes of sinusoidal dilatation and steatosis and elevated the serumalanine aminotransferase, aspartate aminotransferase and alkaline phosphatase levels. Cisplatin generated oxidative stress in the liver which was observed from significant increase lipid peroxidation and reduction in the level of antioxidant mechanisms of glutathione, catalase and superoxide dismutase. Administration of6-hydroxyflavone and silymarin protected the liver from cisplatin-induced degenerative changes and reduced the escalated levels of biochemical parameters. These protective doses also significantly inhibited the generation of oxidative stress as significant attenuation of lipid peroxidation and an increase in the antioxidant status were observed in the cisplatin-injected animals. 
 Conclusion: These findings suggest that 6-hydroxyflavonehas prospective hepatoprotective effect mediated by inhibition of oxidative stress in the hepatocytes and thus can be considered when treating cancer patients with chemotherapeutic drugs including cisplatin. 

Antioxidants from Annatto Seeds as Possible Inhibitory Agents of the Hepatotoxicity Induced by the Antitumor Agent Cisplatin

The effects of annatto seeds and of bixin on the oxidative damage induced by cisplatin in male Wistar rats was evaluated in the present study by way of lipid peroxidation, weight gain, the food efficiency coefficient, fat deposits in the hepatocytes and dosing of the enzymes in this organ. The animals were divided into four groups: control group (CG), cisplatin group (CPG), bixin+cisplatin group (CBG) and annatto+cisplatin group (CUG). Cisplatin (5 mg/kg body weight) was injected intraperitoneally 48 hours before the end of the experiment. The bixin and annatto were administered daily together with the commercial feed. The pre-treatment with annatto and bixin attenuated the cisplatin-induced liver damage and significantly reduced the enzymes AST and ALT. Annatto was shown to be capable of inhibiting lipid peroxidation as determined by TBARS. These results suggest that annatto seeds and bixin could be important agents in the reduction of cisplatin-induced hepatotoxicity.

Hepatoprotective Effect of Oleuropein against Cisplatin-Induced Liver Damage in Rat

Hepatoprotective Effect of Oleuropein against Cisplatin-Induced Liver Damage in Rat

Amelioration of cisplatin-induced hepatotoxicity by statins in rats

Aim: This study was aimed to investigate the effect of simvastatin (SIM) and rosuvastatin (ROS) on the extent of tissue damage in cisplatin (CIS) induced hepatotoxicity. Methodology: Hepatotoxicity was induced in rats with single intraperitoneal injection of 7 mg/kg cisplatin. Group 1 received 0.5% sodium carboxy methyl cellulose, group 2 and 3 received SIM and ROS, respectively, and group 4 was injected single dose of CIS (7 mg/kg, i.p.).Group 5 and 6 were treated with SIM (10 mg/kg, p.o.) and ROS (10 mg/kg, p.o.) daily from 5 days before to 5 day after intraperitoneal administration of CIS, respectively. Liver function tests like AST, ALT and Total bilirubin, and markers of oxidative stress such as liver malondialdehyde (MDA) level, superoxide dismutase (SOD), catalase (CAT) activities and reduced glutathione (GSH) were measured. All tissues were investigated for histopathological changes. Results: CIS treated rats showed a significant increase in AST, ALT and total bilirubin. Moreover, cisplatin caused liver damage with a higher MDA level, depletion of SOD, CAT activity and GSH. SIM and ROS ameliorate CIS induced liver damage due to improvement in liver function, oxidative stress, and histological alteration. Conclusions: These finding suggests that simvastatin and rosuvastatin may have a protective effect against cisplatin-induced liver damage via amelioration of lipid peroxidation as well as due to improvement of liver function.

Licochalcone A Inhibits the Growth of Colon Carcinoma and Attenuates Cisplatin‐Induced Toxicity without a Loss of Chemotherapeutic Efficacy in Mice

Although chemotherapy has an important function in the treatment of most solid tumours, its clinical applications are limited by severe side effects such as nephrotoxicity, hepatotoxicity, ototoxicity and neurotoxicity. Recently, a growing amount of attention has been focused on the investigation of the effects of chemopreventive agents on the inhibition of cancer cell growth and toxicity in combination with chemotherapeutics. The aim of this study was to determine whether licochalcone A (LCA) has the potential to serve as a beneficial supplement during cisplatin chemotherapy. We found that the administration of LCA alone significantly inhibited the size of the solid tumours in CT-26 cell-inoculated Balb/c mice, without any detectable induction of nephrotoxicity, hepatotoxicity and oxidative stress. LCA also suppressed cell proliferation by reducing DNA synthesis of CT-26 murine colon cancer cells in a dose-dependent manner. LCA did not affect the therapeutic efficacy of cisplatin. Furthermore, LCA inhibited the cisplatin-induced kidney damage characterized by increases in the serum creatinine and blood urea nitrogen, as well as the cisplatin-induced liver damage characterized by increases in the serum alanine aminotransferase and aspartate aminotransferase. The repeated oral administration of LCA prior to cisplatin treatment exerted a preventive effect on the cisplatin-mediated increases in the serum nitric oxide and the tissue lipid peroxidation levels, and recovered the depleted reduced glutathione levels in the tissues. These results suggest that supplementation with LCA may be beneficial in counteracting the side effects of cisplatin therapy in cancer patients.

Isoliquiritigenin Inhibits Tumor Growth and Protects the Kidney and Liver Against Chemotherapy-Induced Toxicity in a Mouse Xenograft Model of Colon Carcinoma

A growing amount of attention has been focused on the investigation of the effects of chemopreventive agents on the inhibition of cancer cell growth and toxicity in combination with chemotherapeutics. The objective of this study was to determine whether isoliquiritigenin (ISL) has the potential to serve as a beneficial supplement during cisplatin chemotherapy. We found that the administration of ISL alone significantly reduced the size of the solid tumors in CT-26 cell–inoculated BALB/c mice, without any detectable induction of nephrotoxicity, hepatotoxicity, and oxidative stress, and ISL reduced the viability and DNA synthesis of CT-26 murine colon cancer cells in a dose-dependent manner. ISL did not affect the therapeutic efficacy of cisplatin. Furthermore, ISL suppressed cisplatin-induced kidney damage characterized by increases in serum creatinine and blood urea nitrogen, as well as cisplatin-induced liver damage characterized by increases in serum alanine aminotransferase and aspartate aminotransferase. The repeated oral administration of ISL prior to cisplatin treatment exerted a preventive effect on cisplatin-mediated increases in serum nitric oxide and tissue lipid peroxidation levels, and it recovered depleted GSH levels in the tissues. Therefore, supplementation with ISL may be an effective approach to counteracting the side effects of cisplatin therapy in cancer patients.

Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats

Cisplatin, one of the most active cytotoxic agents against cancer, has several toxicities. Hepatotoxicity is one of them occurred during high doses treatment. The aim of this study was to determine the effects of erdosteine against cisplatin-induced liver injury through tissue oxidant/antioxidant parameters and light microscopic evaluation. The rats were randomly divided into three groups: control (n=5), cisplatin (10 mg/kg, n=6) and cisplatin+erdosteine (50 mg/kg/day oral erdosteine, n=8) groups. The rats were sacrificed at the 5th day of cisplatin treatment. The liver tissues were examined with light microscopy and oxidant/antioxidant biochemical parameters. The malondialdehyde (MDA) and nitric oxide (NO) levels were increased in the cisplatin group in comparison with the control and cisplatin+erdosteine groups (p<0.05). There was no significant difference in MDA and NO levels between control and cisplatin+erdosteine groups. The activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were higher in cisplatin+erdosteine group than cisplatin group (p<0.05). However, the CAT and GSH-Px activities were significantly lower in cisplatin group than in control group (p<0.05). The light microscopic examination revealed that cytoplasmic changes especially around cells of central vein were observed in cisplatin group. Hepatocellular vacuolization was seen in these cells. In the cisplatin plus erdosteine group, a decrease in cytoplasmic changes with the hepatocytes and sinusoidal dilatations around cells of central vein were noticed in as compared to cisplatin group. In the light of microscopic and biochemical results, it was concluded that cisplatin-induced liver damage in high dose and erdosteine prevented this toxic side effect by the way of its antioxidant and radical scavenging effects.

Hepatotoxicity Associated with Cisplatin Chemotherapy

To report a case of possible cisplatin-associated hepatotoxicity. A 69-year-old man received three cycles of cisplatin (100 mg/m2) and fluorouracil (1000 mg/m2/d for five days) for management of squamous cell carcinoma of the head and neck. Liver enzyme concentrations were within normal limits prior to each cycle of therapy but the aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase concentrations increased on the second day of each cycle. The concentrations began to decline on day 3 of each course, despite continued fluorouracil administration, and returned to normal by day 10. The patient's antiemetic therapy included metoclopramide in cycle 1 and ondansetron in cycles 2 and 3, which may have contributed to the enzyme elevations. Case reports of cisplatin-associated hepatotoxicity are reviewed. An association between cisplatin administration and hepatotoxicity is proposed in this patient. This patient may have experienced cisplatin-induced liver damage. Metoclopramide and ondansetron may have contributed to this effect.