Hepatic Glutathione S-transferase Activity Research Articles

Histopathological findings on Carassius auratus hepatopancreas upon exposure to acrylamide: correlation with genotoxicity and metabolic alterations

Acrylamide is an amide used in several industrial applications making it easily discharged to aquatic ecosystems. The toxicity of acrylamide to aquatic organisms is scarcely known, although previous studies with murine models provided evidence for deleterious effects. To assess the effects of acrylamide to freshwater fish, goldfish (Carassius auratus L.) were exposed to several concentrations of waterborne acrylamide and analysed for genotoxic damage, alterations to detoxifying enzymes and histopathology. Results revealed a dose-dependent increase in total DNA strand breakage, the formation of erythrocytic nuclear abnormalities and in the levels of hepatic cytochrome P4501A (CYP1A) and glutathione S-transferase (GST) activity. In addition, acrylamide induced more histopathological changes to pancreatic acini than to the hepatic parenchyma, regardless of exposure concentration, whereas hepatic tissue only endured significant alterations at higher concentrations of exposure. Thus, results confirm the genotoxic potential of acrylamide to fish and its ability to induce CYP1A, probably as a direct primary defence mechanism. This strongly suggests the substance's pro-mutagenic potential in fish, similarly to what is known for rodents. However, the deleterious effects observed in the pancreatic acini, more severe than in the liver, could indicate a specific, albeit unknown toxic mechanism of acrylamide to fish that overran the organism's metabolic defences against a chemical agent rather than causing a general systemic failure.

울금(Curcuma longa L.)이 고지방·고콜레스테롤 식이 흰쥐의 항산화계 및 산화적 손상에 미치는 영향

본 연구는 흰쥐에 고지방·고콜레스테롤 식이와 함께 울금 분말을 농도별로 2.5%(TPA group), 5%(TPB gorup)의 수준으로 공급하였을 시 항산화계 및 산화적 손상에 미치는 영향을 관찰하였다. SOD 활성을 간조직에서 관찰한 결과, 울금 분말을 공급한 군에서 HF군에 비해 SOD 활성이 증가하였으며, 특히 TPB군에서는 유의적으로 증가하였다. GPx 활성은 정상군에 비해 HF군에서 감소되었으나, 울금 분말을 공급한 군에서 HF군에 비해 GPx 활성이 유의적으로 증가되었다. Catalase를 관찰한 결과는 정상군에 비해 고지방·고콜레스테롤군에서 감소되었으며 울금 분말을 공급한 군에서는 증가되었다. Superoxide radical 함량을 간조직의 microsome에서는 정상군에 비해 HF군에서 증가되었으나 울금 분말을 공급한 모든 군에서 감소되었다. 간조직의 mitochondria에서는 정상군에 비해 HF군에서 유의적으로 증가하였고, 울금 분말을 공급한 모든 군에서는 감소하였다. 특히 TPB군에서는 유의적으로 감소하는 것을 볼 수 있었다. 간조직의 mitochondria에서 H2O2의 함량은 정상군에 비해 HF군에서 유의적으로 증가되었다. 울금 분말을 공급한 모든 군에서는 HF군에 비해 감소되었으며 정상군 수준으로 감소되었다. 간조직의 cytosol에서는 정상군에 비해 HF군에서 유의적으로 증가되었으나 울금 분말을 공급한 군에서는 감소되었으며 정상군 수준으로 감소되었다. 간조직의 산화 단백질의 생성지표인 carbonyl 가 함량을 mitochondria에서 측정한 결과 정상군에 비해 고지방·고콜레스테롤군에서 증가되었으며, HF군에 비해 울금 분말을 공급한 모든 군에서 유의적으로 감소하는 경향을 나타내었다. 간조직에서의 TBARS를 측정한 결과 HF군에 비해 울금 분말을 공급한 모든 군에서 유의적으로 감소하는 경향을 나타내었다. 이러한 결과로부터 국내산 울금은 고콜레스테롤 식이 흰쥐에서 항산화계를 강화시켜 조직의 산화적 손상을 감소시키는 항산화 효과가 있음이 규명되었다.

Inhibitory effect of anthocyanidins on hepatic glutathione S-transferase, UDP-glucuronosyltransferase and carbonyl reductase activities in rat and human

1. Anthocyanins and their aglycone anthocyanidins represent the most abundant flavonoids in human diet and popular constituents of various dietary supplements. The aim of this study was to evaluate inhibitory effect of four anthocyanidins (delphinidin, cyanidin, malvidin and pelargonidin) on three families of important drug-metabolizing enzymes: carbonyl reductases (CBRs), glutathione S-transferases (GSTs) and UDP-glucuronosyltransferases (UGT).2. Human or rat hepatic subcellular fractions were incubated with or without pure anthocyanidins (100 µM) and the activities of CBR, GST and UGT were assayed using menadione, 1-chloro-2,4-dinitrobenzene and p-nitrophenol as substrates, respectively. For the most potent inhibitors, half maximal inhibitory concentrations (IC50) were determined and the inhibition kinetics study was performed.3. Anthocyanidins inhibited weakly the activity of GST and moderately the activities of CBR and UGT. Cyanidin was the most potent inhibitor of human UGT with IC50 = 69 µM (at 200 µM substrate concentration) and competitive type of action. Delphinidin acted as significant non-competitive inhibitor of human CBR with IC50 = 16 µM (at substrate concentration 500 µM). The inhibitory potency of anthocyanidins differed in rat and human samples significantly.4. Anthocyanidins are able to inhibit CBR and UGT in vitro. Possible interference of anthocyanidins (in high-dose dietary supplements) with simultaneously administered drugs, which are UGT or CBR substrates, should be checked.

Japanese Butterbur (Petasites japonicus) Leaves Increase Hepatic Oxidative Stress in Male Rats

We investigated the adverse effects of Japanese butterbur leaves (Petasites japonicus, Compositae) in male F344/DuCrj rats. The rats were fed a control diet or a treatment diet containing 5% butterbur leaf powder for 4 weeks. No differences were observed in body weight gain, food intake or feed efficiency between treatments, but relative liver weight in the butterbur group was significantly higher than that of the control group. In addition, thiobarbituric acid reactive substances (TBARs) and glutathione levels in the serum and liver of the butterbur group were higher than those of the control group. Hepatic glutathione reductase and glutathione S-transferase activities and mRNA expression in the butterbur leaf group were higher than in the control group. Furthermore, hepatic cytochrome 2E1 mRNA expression was higher than in the control group. In vitro, an acetone extract of the butterbur leaf powder showed the strongest increase in TBARs level in a hepatic homogenate through 4 d. Our findings suggest that feeding 5% butterbur leaf powder to rats can cause adverse effects by increasing oxidative stress.

High-dose sodium selenite toxicity cannot be prevented by the co-administration of pharmacological levels of epigallocatechin-3-gallate which in turn aggravates the toxicity

Selenium, an essential trace element, can also be toxic at higher levels of exposure. Several lines of evidence show epigallocatechin-3-gallate (EGCG), a predominant component of green tea catechins with numerous health benefits, can ameliorate the toxicity of many agents. A proof-in-principle experiment was conducted to determine if EGCG would ameliorate sodium selenite-induced growth suppression. Mice were intraperitioneally injected with selenite once daily for five days at a dose of 3mg Se/kg, which fully suppressed animal growth but did not cause death. Surprisingly the co-administration of the selenite and nontoxic doses of EGCG (10, 20 and 40mg/kg, intraperitioneally) resulted in the mortality of treated mice in a dose and time-dependent manner (33.3%, 100% and 100%, respectively). EGCG-selenite induced lethality did not result from enhanced selenium accumulation but appeared to involve the suppression of a selenite-induced adaptive response as evidenced by hepatic glutathione S-transferase activity. While EGCG has been reported to ameliorate the toxicity of some agents, the induction of mortality by combined treatment with pharmacological doses of selenium and EGCG is a previously unrecognized synergism that must be considered not only in the remediation of high environmental selenium exposures but also in the development of pharmaceuticals and nutriceuticals.

Effect of Zingiber officinale on liver oxidative status and biochemical parameters in rats exposed to paraquat

Oxidative stress caused by reactive oxygen species is one of the major pathogenesis of important diseases of animals and human. Paraquat is widely used as herbicide. The toxicity of paraquat is through induction of oxidative processes in biological systems. Biochemically, this herbicide interferes with intracellular electron transfer system leading to the formation of superoxide anion. Zingiber officinale (ginger) is widely used as a spice and medical treatment for various diseases. The objective of this study was to assess the effect of different levels of ginger extract on antioxidant status and serum metabolites of rats. Sixty male albino Wistar rats were divided in six groups as follows: control (saline); ginger; paraquat; paraquat with 100, 200, and 400 ginger. After 30 days of treatment, the blood was collected by cardiac puncture. The activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST), reduced glutathione (GSH), and lipid peroxidation were estimated. In paraquat-treated group, the serum levels of ALT, AST, and malondialdehyde (MDA) were markedly raised. Administration of ginger extract with paraquat reduced the serum levels of ALT, AST, and MDA. Hepatic SOD, CAT, GPx, GST, and GSH activities were significantly decreased in paraquat-treated group compared to those of control. However, concurrent administration of paraquat with all concentrations of ginger extract had the opposite effect, where it increased the hepatic SOD, CAT, GPx, GST, and GSH activities near to control. The present study demonstrates that administration of ginger extract to rats modulates the antioxidant enzymes and suggests a possible adaptive mechanism to counteract oxidative stress situation.

Fuzzy logic and adaptive neuro-fuzzy inference system for characterization of contaminant exposure through selected biomarkers in African catfish

This study represents a first attempt at applying a fuzzy inference system (FIS) and an adaptive neuro-fuzzy inference system (ANFIS) to the field of aquatic biomonitoring for classification of the dosage and time of benzo[a]pyrene (BaP) injection through selected biomarkers in African catfish (Clarias gariepinus). Fish were injected either intramuscularly (i.m.) or intraperitoneally (i.p.) with BaP. Hepatic glutathione S-transferase (GST) activities, relative visceral fat weights (LSI), and four biliary fluorescent aromatic compounds (FACs) concentrations were used as the inputs in the modeling study. Contradictory rules in FIS and ANFIS models appeared after conversion of bioassay results into human language (rule-based system). A "data trimming" approach was proposed to eliminate the conflicts prior to fuzzification. However, the model produced was relevant only to relatively low exposures to BaP, especially through the i.m. route of exposure. Furthermore, sensitivity analysis was unable to raise the classification rate to an acceptable level. In conclusion, FIS and ANFIS models have limited applications in the field of fish biomarker studies.

칡(Pueraria thunbergiana)추출물 청국장 캡슐의 ob/ob Mice에 대한 항비만 효과

본 연구는 칡청국장 및 칡청국장 캡슐함유 식이가 체중, 지방축적, 지질대사 등에 미치는 효능을 알아보기 위하여 선천성 비만 및 인슐린 비의존성 당뇨병의 모델동물인 ob/ob마우스를 대상으로 정상대조군(NC: 일반식이군), 양성대조군(PC: 2% 청국장함유군), 칡청국장 2% 함유군(AR: 2% 칡청국장), 칡청국장 캡슐군(ARC: 2% 칡청국장 캡슐함유)으로 나누어 10주간 실험하였다. 체중 및 식이효율은 칡청국장 캡슐군에서 정상대조군에 비하여 유의하게 감소하였다. 혈청 콜레스테롤, LDL-콜레스테롤, 중성지방, 혈당 및 동맥경화지수는 칡청국장 캡슐군에서 정상대조군에 비하여 유의하게 감소하였다. 칡청국장 캡슐군에서 지방간의 전형적인 지방축적의 억제효과를 보였다. 간조직의 SOD, CAT, GST 활성은 칡청국장 캡슐군에서 정상대조군에 비하여 유의하게 증가하였다. 이에 칡 추출물 청국장 및 캡슐형태의 투여는 지방함량의 저하효과, 혈당강하효과, 항산화계의 활성도 증가 등의 효과를 통하여 항비만기능이 있으며, 칡청국장 캡슐형의 기능성이 높다는 사실을 확인할 수 있었다.

Hepatic Metallothionein and Glutathione-S-Transferase Responses in Two Populations of Rice Frogs, Fejervarya limnocharis, Naturally Exposed to Different Environmental Cadmium Levels

Glutathione-S-Transferase (GST) and metallothionein are important biomarker endpoints in studying the effect of Cd exposure. The purpose of this research was to study the correlation between hepatic GST and metallothionein with hepatic Cd in wild Fejervarya limnocharis exposed to environmental Cd. Results showed that frogs from contaminated sites had significantly higher hepatic metallothionein (3.58 mg/kg wet weight) and GST activity (0.259 μmol/min/mg total protein) than those from the reference site (2.36 mg/kg wet weight and 0.157 μmol/min/mg total protein respectively). There was a significantly positive correlation between hepatic Cd and GST activity (r = 0.802, p = 0.009) but not between hepatic Cd and metallothionein (r = 0.548, p = 0.139). The results concluded that while frogs from the contaminated site had higher GST and metallothionein, only GST showed significant positive correlation with hepatic Cd levels, indicating that hepatic GST activity may be used as a biomarker endpoint.

Antioxidant effect of grapevine leaves extract in rats fed a high fat diet

The purpose of this study was to investigate the effect of grapevine leaves extract(GLE) on oxidative stress in rats fed a high fat diet. The 4‐week‐old Sprague‐Dawley rats were divided into six groups; nomal diet group(N), nomal diet +1.0% GLE group(NG1.0), nomal diet +1.5% GLE group(NG1.5), high fat diet group(HF), high fat diet +1.0% GLE group(HFG1.0), high fat diet +1.5 GLE group(HFG1.5). Rats of each group were fed on the corresponding diets for 6 weeks. The thiobarbituric acid reactive substances(TBARS) in high fat and GLE‐treated groups revealed a significant reduction in liver, erythrocytes and plasma compared with the HF group. The erythrocytic activities of catalase(CAT), superoxide dismutase(SOD) and glutathione peroxidase(GSH‐Px) in HFG1.5 group were significantly higer than those of HF group. The hepatic activities of GSH‐Px and glutathione S‐transferase( GST) increased in GLE‐supplemented high fat group compered with HF group. The liver levels of retinol and tocopherol significantly increased in HFG1.5 group compared with those of HF group. Plasma tocopherol level in HFG1.5 group was significantly higher than HF group. These results indicate that grapevine leaves extract exerts a protective effect on high fat diet‐induced oxidative stress in rats. This research was supported by¡°Region‐specific agriculture Development project of RDA(Rural Development Administration), Republic of Korea.

Evaluation of spatial and temporal changes in biomarker responses in the common carp (Cyprinus carpio L.) for biomonitoring the Meriç Delta, Turkey

The aim of this study is to examine the activity of several biomarkers in carp, Cyprinus carpio L., to determine their response to xenobiotics, such as organochlorine pesticides (OCPs), in the Meriç Delta. Fish were collected from contaminated sites and from areas regarded as relatively less contaminated in four sampling periods. Hepatic glutathione S-transferase (GST), carboxylesterase (CaE), lactate dehydrogenase, aspartate aminotransferase, and acid phosphatase activities were measured as biomarkers in the fish. For all fish, the condition factor and hepatosomatic index, were calculated to determine the condition of the fish. The results of this study indicated that the mean GST activity showed an increase in fish from the Meriç-Ergene junction site and a decrease in Enez site with respect to fish from Meriç site. Furthermore, the study shows that spatial and temporal changes of biomarkers such as GST and CaE might be useful for the assessment of environmental contamination in the Meriç Delta.

Protective effect of Danning tablet on acute livery injury with cholestasis induced by α-naphthylisothiocyanate in rats

Ethnopharmacological relevanceDanning tablet, as a composite prescription of traditional Chinese medicine, has been used clinically to relieve liver and gallbladder diseases in China. However, the mechanisms involved are still unclear. Aim of the studyThe present investigation was designed to assess the effects and possible mechanisms of Danning tablet on α-naphthylisothiocyanate (ANIT)-induced liver injury with cholestasis. Materials and methodsDanning tablet (3, 1.5 or 0.75g/kg body weight/day) was intragastrically (i.g.) given to experimental rats for seven days before they were treated with ANIT (60mg/kg daily via i.g.) which caused liver injury. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (γ-GTP), total bilirubin (T-Bil), direct bilirubin (D-Bil), total bile acid (TBA) and bile flow were measured to evaluate the protective effect of Danning tablet at 48h after ANIT treatment. Furthermore, protective mechanisms of Danning tablet against ANIT-induced liver injury were elucidated by assays of liver enzyme activities and component contents including myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (Gpx), catalase (CAT) and glutathione S-transferase (GST), as well as liver lipid peroxide (LPO) and glutathione (GSH). The biochemical observations were supplemented by histopathological examination. Phytochemical analysis of Danning tablet was performed by UPLC-MASS. ResultsObtained results demonstrated that high dose (3g/kg) of Danning tablet significantly prevented ANIT-induced changes in bile flow (P<0.01), and serum levels of ALT, AST, ALP, γ-GTP, T-Bil, D-Bil (P<0.01) and TBA (P<0.05). In addition, ANIT-induced increases in hepatic MPO, GST activities and GSH, LPO contents were significantly (P<0.01) reduced, while SOD, Gpx, CAT activities in the liver tissue which were suppressed by ANIT were significantly (P<0.01) elevated in the groups pretreated with Danning tablet at the dose of 3g/kg B.W. Histopathology of the liver tissue showed that pathological injuries were relieved after Danning tablet (3g/kg) pretreatment. The results also showed that medium dose (1.5g/kg) of Danning tablet exhibited partially protective effect on ANIT-induced liver injury with cholestasis by reversing part of biochemical parameters and histopathological changes. Low dose (0.75g/kg) of Danning tablet did not show any protective effect on ANIT-induced liver injury with cholestasis. Phytochemical analyses revealed the presence of anthraquinones, flavonoids and stilbene in the Danning tablet. ConclusionThese findings indicate that Danning tablet exerts a dose-dependently protective effect on ANIT-induced liver injury with cholestasis in rats, and the possible mechanism of this activity is likely due to its attenuation of oxidative stress in the liver tissue and neutrophil infiltration.

Hydrogen sulfide-releasing aspirin modulates xenobiotic metabolizing enzymes in vitro and in vivo

The balance between phase-I carcinogen-activating and phase-II detoxifying xenobiotic metabolizing enzymes is critical to determining an individual's risk for cancer. We evaluated the effect of Hydrogen sulfide-releasing aspirin (HS-ASA) on xenobiotic metabolizing enzymes in HT-29 human colon and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Wistar rats. HS-ASA inhibited the growth of HT-29 and Hepa 1c1c7 cells, with an IC50 of 3.2±0.3μM and 4.2±0.4μM, respectively. The IC50 for ASA in both cell lines was greater than 5000μM at 24h. In these cell lines, HS-ASA caused a dose-dependent increase in activity and expression of the phase-II enzymes glutathione S-transferase (GST) and NAD(P)H:quinoneoxireductase (NQO1). It also caused an increase in UDP-glucuronosyltransferase (UGT) expression. The levels of CYP 1A1 a phase-I enzyme was increased by HS-ASA in both cell lines. Pretreatment of cells with NaF, an esterase inhibitor, abrogated the HS-ASA-mediated increases in NQO1 enzyme activity. HS-ASA increased the protein levels of the transcription factor Nrf2, which is a regulator of the phase-II enzymes. In vivo, HS-ASA at 100mg/kg/day had no effect on rat's weights; it induced a 3.4-fold and 1.4-fold increase in hepatic GST and NQO1 enzyme activities, respectively. GST and NQO1 protein levels were also increased. In contrast to that in cultured cells, CYP 1A1 protein levels were not altered in vivo. Therefore, HS-ASA induces phase-II enzymes, at least in part, through the action of H2S and by modulating Nrf2; these effects may be part of its mechanism of action against carcinogenesis.

Combined effect of vanadium and nickel on lipid peroxidation and selected parameters of antioxidant system in liver and kidney of male rat

In this investigation, hepatorenal antioxidant effects of combined oral administration of ammonium metavanadate (AMV; 0.15 mg V/ml) and nickel sulfate (NS; 0.18 mg Ni/ml) in male albino rats over a 21- day period have been evaluated. After administration of vanadium, lipid peroxidation (LPO) increased significantly (p 0.05) in liver, superoxide dismutase (SOD) and glutathione –S-transferase (GST) activities increased significantly in kidney (p < 0.01) and decreased in liver (p < 0.001) whereas glutathione (GSH) content decreased (p < 0.001) in both organs. The exposure to nickel led to a significant decrease (p < 0.001) in SOD, GST activities in liver and GSH content in kidney and a significant (p < 0.001) increase in the hepatic MDA content and renal SOD activity. When the metals were administered in combination, the elevation of lipid peroxidation did not potentiate. However, the inhibition in hepatic SOD was augmented. In the other hand, the combined metals treatment slightly improved the decreased hepatic GST activity and induced the hepatorenal content of GSH. Signs of toxicity were observed following treatment with vanadium, not nickel nor combined vanadium and nickel. A reduction in cellular enzymatic (SOD) and non-enzymatic (GSH) antioxidants is clearly indicative of oxidative stress. The results of this study indicate that kidney is more vulnerable to the caused by vanadium and/or nickel-induced oxidative stress than liver, the oxidative capacity of nickel is much lower than vanadium as well as that the oxidative capacity of combined vanadium and nickel may be more markedly decreased than at separate exposure. Key words: Oral, vanadium, nickel, antioxidant, hepatorenal, rats.

Artificial neural network modeling of biomarkers to infer characteristics of contaminant exposure in Clarias gariepinus

This study examined the potential of artificial neural network (ANN) modeling to infer timing, route and dose of contaminant exposure from biomarkers in a freshwater fish. Hepatic glutathione S-transferase (GST) activity and biliary concentrations of BaP, 1-OH BaP, 3-OH BaP and 7,8D BaP were quantified in juvenile Clarias gariepinus injected intramuscularly or intraperitoneally with 10–50 mg/kg benzo[ a]pyrene (BaP) 1–3 d earlier. A feedforward multilayer perceptron (MLP) ANN resulted in more accurate prediction of timing, route and exposure dose than a linear neural network or a radial basis function (RBF) ANN. MLP sensitivity analyses revealed contribution of all five biomarkers to predicting route of exposure but no contribution of hepatic GST activity or one of the two hydroxylated BaP metabolites to predicting time of exposure and dose of exposure. We conclude that information content of biomarkers collected from fish can be extended by judicious use of ANNs.

Biotransformation modulation and genotoxicity in white seabream upon exposure to paralytic shellfish toxins produced by Gymnodinium catenatum

Fish are recurrently exposed to paralytic shellfish toxins (PSTs) produced by Gymnodinium catenatum. Nevertheless, the knowledge regarding metabolism of PSTs and their toxic effects in fish is scarce. Consequently, the current study aims to investigate the role of phase I and II detoxification enzymes on PST metabolism in the liver of white seabream ( Diplodus sargus), assessing ethoxyresorufin- O-deethylase (EROD) and glutathione S-transferase (GST) activities. Moreover, the genotoxic potential of PSTs was examined through the erythrocytic nuclear abnormality (ENA) assay. Fish were intracoelomically (IC) injected with a nominal dose (expressed as saxitoxin equivalents) of 1.60 μg STXeq kg −1 semipurified from a G. catenatum cell culture with previously determined toxin profile. Fish were sacrificed 2 and 6 days after IC injection. PST levels determined in fish liver were15.2 and 12.2 μg STXeq kg −1, respectively, at 2 and 6 days after the injection. Though several PSTs were administered, only dcSTX was detected in the liver after 2 and 6 days. This was regarded as an evidence that most of the N-sulfocarbamoyl and decarbamoyl toxins were rapidly biotransformed in D. sargus liver and/or eliminated. This was corroborated by a hepatic GST activity induction at 2 days after injection. Hepatic EROD activity was unresponsive to PSTs, suggesting that these toxins enter phase II of biotransformation directly. The genotoxic potential of PSTs was also demonstrated; these toxins were able to induce cytogenetic damage, such as chromosome (or chromatid) breaks or loss and segregational anomalies, measured by the ENA assay. Overall, this study pointed out the ecological risk associated with the contamination of fish with PSTs generated by G. catenatum blooms, providing the necessary first data for a proper interpretation of biomonitoring programs aiming to assess the impact of phytoplankton blooms in fish.

Potential adverse effects of oseltamivir in rats: males are more vulnerable than females

Oseltamivir is the most widely used antiviral drug for the treatment and prophylaxis of influenza. However, not much is known about its adverse effects. The potential side effects were investigated in male and female rats (140-170g). Oseltamivir was administered at 2.2mg·kg(-1)·day(-1) for 5days. For both genders, treatment with oseltamivir resulted in significant reductions in the hepatic activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase. Also for both genders, oseltamivir produced modest reductions in the hepatic activities of UDP-glucuronosyltransferase, quinone oxidoreductase, thioredoxin reductase, CYP1A1/2, and CYP3A, as well as hepatic glutathione content. For both genders, neither the kidney functions nor protein profile was affected by oseltamivir. Oseltamivir also caused significant elevation in serum levels of both triacylglycerols and LDL-cholesterol and in the activity of γ-glutamyl transpeptidase, in both genders. For male animals only, oseltamivir treatment elevated the serum level of total cholesterol as well as the activity of serum alanine aminotransferase, and reduced the hepatic activities of superoxide dismutase and catalase. Oseltamivir caused oxidative stress and acute toxicity in the liver, and disrupted the cholesterol and lipid metabolism but was less likely to cause serious drug interactions. There was a sexual differentiation in these adverse effects, with adverse effects being more evident in male rats.

Effectiveness of Melatonin, as a Radiation Damage-Mitigating Drug in Modulating Liver Biochemical disorders in γ-Irradiated Rats

MELATONIN has an antiperoxidative effect on several tissues as well as a scavenger effect on reactive oxygen species (ROS). Whilst radiation-hazards due to free radical generation, present enormous challenges for biological and medical safety. Therefore, rats were classified into four groups; control (n= 8), (received 0.5 ml of alchoholic saline as a vehicle for 5 days). Melatonin-treated rats received 10 mg/ kg body wt, for 5 days (given to the animals in the morning via stomach tube). γ-irradiated rats received 0.5 ml of the melatonin vehicle followed by one shot dose of 3 Gy γ-rays. Each of these groups was compared with a further group, which-received melatonin for 5 days after 3 Gy γ-irradiation exposure. The results revealed that all considered biochemical parameters were not changed significantly in melatonin-treated group as compared with control one. In the liver tissue of the γ-irradiated animals (3 Gy), the oxidative stress markers malondialdehyde (MDA) and protein carbonyl (PC) were significantly increased, while a marked decrease occurred in the contents of deoxy- & ribo-nucleic acids (DNA & RNA) and glutathione (GSH) as well as activity of glutathione-S-transferase (GST). In addition, catalase (CAT) and myeloperoxidase (MPO) activities were increased. Activities of aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) were significantly increased in sera of the irradiated rats. Treatment with melatonin for 5 days after γ-rays exposure significantly modulated the radiation-induced elevations in MDA and PC levels in the liver tissue and significantly restored hepatic GSH content, GST, CAT and MPO activities. Post-irradiation treatment with melatonin showed significant higher hepatic DNA and RNA contents than irradiated rats. The activities of AST, ALP, and GGT in serum were significantly ameliorated when melatonin was administrated after irradiation.

Abstract 807: Hydrogen sulfide-releasing aspirin modulates xenobiotic metabolizing enzymes in vitro and in vivo

Abstract Introduction: Xenobiotic metabolizing enzymes are classified as phase-I (oxidation/reduction) and phase-II (conjugation) enzymes; the balance between the phase-I carcinogen-activating enzymes and the phase-II detoxifying enzymes may be important in determining an individual's risk for cancer. Hydrogen sulfide-releasing aspirin (HS-ASA) is a new compound with significant anti-inflammatory properties. It consists of ASA covalently attached to 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione, which releases hydrogen sulfide. Our initial studies indicate that HS-ASA has chemopreventive properties. In the present study, we evaluated the effect of HS-ASA on xenobiotic metabolizing enzymes both in vitro and vivo. Methods: HS-ASA was synthesized and purified by us with 1H-NMR verification. Cell lines: HT-29 human colon adenocarcinoma and Hepa 1c1c7 mouse liver adenocarcinoma. Cell growth inhibition: MTT. Levels of cytochrome P450 1A1 (CYP 1A1) a phase-1 enzyme and NAD(P)H:quinone oxireductase (NQO), glutathione S-transferase (GST) and UDP-glucuronyltransferase (UGT), phase-II enzymes by immunoblots. Enzyme activity: GST and thioredoxin reductase (Trx). In vivo: Male Wistar rats (N = 4/group) were treated via gavage either with vehicle or with HS-ASA 100 mg/kg/day. Weight of animals in each group was recorded every 3 days. After 21 days, animals were killed and liver microsomes and cytosols were prepared for phase-I and phase-II enzyme evaluation. Results: HS-ASA inhibited the growth of HT-29 and Hepa 1c1c7 cells, with an IC50 of 2.5 ± 0.3 µM and 2.9 ± 0.4 µM, respectively. The IC50 for ASA in both cell lines was &amp;gt;5,000 µM at 24h. The ratio ASA/HS-ASA is &amp;gt;2000 in the HT-29 cells and &amp;gt;1700 in Hepa 1c1c7 cells, suggesting that HS-ASA is at least 1700-2000-fold more potent than traditional ASA. In HT-29 cells, at 0.5xIC50, 1xIC50, and 2xIC50, HS-ASA increased GST activity by 2.5-, 7.2-, and 11-fold; and it inhibited Txr by 36 ± 3%, 67 ± 2% and 79 ± 2% respectively. In HT-29 cells, levels of CYP 1A1 were not significantly affected whereas levels of GST and UGT were increased dose-dependently by HS-ASA. In Hepa 1c1c7 cells, levels of NQO were also significantly increased. In vivo, HS-ASA: 1. had no effect on rat's weight; 2. increased hepatic GST activity by 3.4-fold and NQO by 1.4-fold; 3. immunoblots showed significant increases in GST and NQO protein levels but no changes in CYP 1A1 protein levels. Conclusions: HS-ASA co-induces multiple phase-II metabolizing enzymes and thus may be regarded as a monofunctional inducer. This represents one mechanism by which HS-ASA exhibits chemopreventive properties. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 807. doi:10.1158/1538-7445.AM2011-807

Investigation into the cancer protective effect of flaxseed in Tg.NK (MMTV/c-neu) mice, a murine mammary tumor model

The aim of the present study was to investigate whether low flaxseed doses relevant to human dietary exposure can prevent mammary tumors in transgenic Tg.NK mice, a model of breast cancer. Animals were exposed to flaxseed through the diet at human relevant levels. Tumor-related parameters and tumor development were evaluated. Hepatic cytochrome P450 and glutathione S-transferase activities were significantly reduced in animals receiving low flaxseed doses. An incidence of palpable tumors before sacrifice, a number of tumors per mouse, and a number of large tumors (>6mm diameter) at necropsy were statistically significantly lower in the high flaxseed group compared to controls, suggesting a beneficial effect on tumor progression of small dietary doses of flaxseed. However, the number of tumor-bearing mice and multiplicity of tumors at necropsy were not statistically significantly lower compared to the controls. Thus, the effect of small dietary doses of flaxseed on mammary tumor development in Tg.NK mice remains to be established.