HEPATOPROTECTIVE POTENTIAL OF EUGENIA?UNIFLORA?L AGAINST GENTAMYCIN INDUCED HEPATOXICITY

Hepatotoxicity is a common drug adverse effect and gentamycin has been linked to hepatotoxic adverse reactions. Folklore and ethnobotanical studies indicate Eugenia uniflora L is used in the treatment of gastrointestinal ailments and has exhibited diverse biological activities. We investigated the hepatoprotective potential of this plant in treating gentamycin-induced hepatoxicity and compared the effect with Celebrex a COX2 selective inhibitor. Twenty-eight male adult Wistar rats average of 225g were used for the study and randomised into groups as described: normal control( normal saline), negative control: Gentamycin (40mg/kg. i.p), positive control; Gentamycin (40mg/kg. i.p) +5mg/kg Celebrex. Extract low dose: Gentamycin (40mg/kg i.p)+(50mg/kg) Eugenia uniflora L. leaves, intermediate-dose: Gentamycin (40mg/kg i.p) +100mg/kg Eugenia uniflora L leaves, high dose : Gentamycin (40mg/kg, i.p)+ (200mg/kg, ) of Eugenia uniflora L leaves. Our findings indicate that the body weight was unaffected throughout the experiment, as clearly demonstrated by the lack of significant variability (p<0.05). Hepatotoxicity was confirmed by dose-dependent alteration in Liver marker enzymes, including AST, ALT, and ALP. Eugenia uniflora L leaves were able to ameliorate the levels of these liver enzymes to a normal level. Liver tissue revealed a dose-dependent curative effect with Eugenia uniflora L compared to the COX2 inhibitor (Celebrex) treatment. Consequently, we hereby report, for the first time, that an aqueous extract of Eugenia uniflora L leaves confers hepatoprotection against gentamycin-induced hepatoxicity in Wistar rats.

Time-and dose-effect of Gardenia Jasminoides extract on hepatoxicity in rats / 中成药

AIM To observe the relationship between dose effect and time effect on hepatoxicity of Gardenia jasminoides Ellis extract in rats.MOTHODS Wistar rats were divided into four groups:low,middle and high (3,10,and 30 g/kg) dose of G.Jasminoides groups (administrated by gavage),and the normal control group were orally given deionized water.All rats were observed daily during the administration period.On the 7th,14th,28th day after the administration,blood samples were collected;serum alanine transaminase (ALT),aspartate transaminase (AST),alkaline phosphatase (ALP),glutamic dehydrogenase (GLDH) activity and total bile acid (TBA) and total bilirubin (TBIL) were determined.The livers were weighed and the liver index was calculated.HE staining and observation of histopathological changes in the structure of liver tissue under light microscopy were performed.RESULTS After the 7th day of administration,the rats in high dose group showed lower food consumption and slowly increased body weight.Serum ALT,AST,ALP,TBA,TBIL and GLDH in rats from high dose group were significantly higher than those in the normal control group.The liver index of rats in the middle and high dose groups was significantly increased than that in the normal control group.After the 14th day of administration,serum ALT,TBA and TBIL in rats from the high dose group were significantly higher than those in the normal group.The liver index of rats in the middle and high dose groups was significantly increased than that in the normal control group.After 28th day of administration,serum ALT and TBA in the rats from the high dose group,TBIL and GLDH in rats from the middle dose group,and GLDH in rats from the low dose group were significantly higher than those in the normal control group.The liver indexes of rats in all dose groups were significantly increased than those in the normal control group.After the 7th,14th or 28th day of the treatment,histopathological changes such as the liver cell hypertrophy,interlobular bile duct hyperplasia,and inflammatory cell infiltration appeared in the middle and high dose groups.CONCLUSION The high dose of G.jasminoides can induce and increase liver toxicity with the increase in dose,but at high dose level,liver toxicity does not increase with time.

Study on the regulation of autophagy against anticancer drugs' toxicity / 药学学报

Autophagy is a crucial biological process in eukaryotes, which is involved in cell growth, survival and energy metabolism. It has been confirmed that autophagy mediates toxicity of anticancer drugs, especially in heart, liver and neuron. It is important to understand the function and mechanism of autophagy in anticancer drugs-induced toxicity. Given that autophagy is a double-edged sword in the maintenance of the function of heart, liver and neuron, the autophagy-mediated toxicity are very complicated in the body. We provide a review on the concept of autophagy and current status about autophagy-mediated toxicity of anticancer drugs. The knowledge is crucial in the basic study of anticancer drugs-induced toxicity, and provides some strategies for the development of alleviating the toxicity of anticancer drugs.

Exploration research on hepatotoxic constituents from Polygonum multiflorum root / 中国中药杂志

By observing the cytotoxic effects of anthraquinones on HepG2 cell and using the precision-cut liver slices technique to authenticate the cytotoxic constituents, the paper aims to explore the material basis of Polygonum multiflorum root to cause liver toxicity. Firstly, MTT method was used to detect the effect of 11 anthraquinone derivatives on HepG2 cell. Then, the clear cytotoxic ingredients were co-cultured with rat liver slices for 6h respectively, and the liver tissue homogenate was prepared. BCA method was used to determine the content of protein in the homogenate and continuous monitoring method was used to monitor the leakage of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamine amino transpeptidase (GGT) and lactate dehydrogenase (LDH). The toxic effect of these ingredients on liver tissue was tested by calculating the leakage rate of the monitored enzymes. As a result, rhein, emodin, physcion-8-O-β-D-glucopyranoside and physcion-8-O-(6'-O-acetyl)-β-D-glucopyranoside showed cytotoxic effects on HepG2 cell and their IC₅₀ values were 71.07, 125.62, 242.27, 402.32 μmol•L⁻¹ respectively, but the other 7 compounds are less toxic and their IC₅₀ values can not be calculated. The precision-cut liver slices tests showed that rhein group of 400 μmol•L⁻¹ concentration significantly increased the leakage rate of ALT, AST and LDH (P<0.01), and the rhein group of 100 μmol•L⁻¹ concentration only increased the leakage rate of LDH (P<0.05). With the increase of rhein concentration, the protein content in liver slices decreased significantly (P<0.05) with a certain range of does. Emodin group of 400 μmol•L⁻¹ concentration significantly increased the leakage rate of ALT, GGT and LDH (P<0.01). Physcion-8-O-β-D-glucopyranoside group of 800 μmol•L⁻¹ concentration also significantly increased the leakage rate of ALT, AST and LDH (P<0.01 or P<0.05), but the group of 200 μmol•L⁻¹ concentration only significantly increased the LDH leakage (P<0.05). Along with the increase of the concentration of physcion-8-O-β-D-glucopyranoside, the leakage rate of ALT, AST and LDH showed a trend of increase, but the protein content in liver slices was in decline. Furthermore, MTT reduction ability of liver slices significantly decreased (P<0.01) in the physcion-8-O-β-D-glucopyranoside group of 800 μmol•L⁻¹ concentration. The results suggested that rhein, emodin and physcion-8-O-β-D-glucopyranoside at high concentrations (≥400 μmol•L⁻¹) can produce some damage to the liver tissue. However, the exposure levels of these constituents are very low, so to reach the toxic concentration (400 μmol•L⁻¹ or 800 μmol•L⁻¹) an adult of 65 kg body weight will need at least a single oral 4 898 g, 339 g and 5 581 g of P.multiflorum root respectively, which is far from the statutory dose of crude P. multiflorum root (3-6 g) or its processed product (6-12 g). Therefore, the conclusion that anthraquinones are the prime constituents of the hepatotoxicity of P. multiflorum root are still not be proved.

Hepatoprotective and immunomodulatory properties of aqueous extract of Curcuma longa in carbon tetra chloride intoxicated Swiss albino mice

<p><b>OBJECTIVE</b>To evaluate the hepatoprotective and immunotherapeutic effects of aqueous extract of turmeric rhizome in CCl4 intoxicated Swiss albino mice.</p><p><b>METHODS</b>First group of mice (n=5) received CCl4 treatment at a dose of 0.5 mL/kg bw (i.p.) for 7 days. Second group was fed orally the aqueous extract of turmeric at a dose of 50 mg/kg bw for 15 days. The third group was given both the turmeric extract (for 15 days, orally) and CCl4 (for last 7 days, i.p.). The fourth group was kept as a control. To study the liver function, the transaminase enzymes (SGOT and SGPT) and bilirubin level were measured in the serum of respective groups. For assaying the immunotherapeutic action of Curcuma longa (C. longa), non specific host response parameters like morphological alteration, phagocytosis, nitric oxide release, myeloperoxidase release and intracellular killing capacity of peritoneal macrophages were studied from the respective groups.</p><p><b>RESULTS</b>The result of present study suggested that CCl4 administration increased the level of SGOT and SGPT and bilirubin level in serum. However, the aqueous extract of turmeric reduced the level of SGOT, SGPT and bilirubin in CCl4 intoxicated mice. Apart from damaging the liver system, CCl4 also reduced non specific host response parameters like morphological alteration, phagocytosis, nitric oxide release, myeloperoxidase release and intracellular killing capacity of peritoneal macrophages. Administration of aqueous extract of C. longa offered significant protection from these damaging actions of CCl4 on the non specific host response in the peritoneal macrophages of CCl4 intoxicated mice.</p><p><b>CONCLUSIONS</b>In conclusion, the present study suggests that C. longa has immunotherapeutic properties along with its ability to ameliorate hepatotoxicity.</p>

N-acetyltransferase2 genotype and its association with hepatitis among Filipino children treated with first line anti-tuberculosis drugs

RATIONALE: Among the first line antituberculosis (anti-TB) drugs, the major drug incriminated in the development of hepatotoxicity is isoniazid (INH). The human N-acetyl transferase2 (NAT2) gene is mainly responsible for INH metabolism. This gene exhibits a hereditarily determined polymorphism. There is presently no study on the predominant NAT2 genotype among Filipinos. There are also no Filipino studies on the incidence of hepatitis and other adverse effects of first line anti-TB drugs. OBJECTIVES: To determine the predominant NAT2 genotype and its association with the development of hepatitis among Filipino children given first line anti-TB drugs (INH, rifampicin and pyrazinamide) and to determine the incidence of hepatitis and other serious adverse reactions to these drugs. STUDY DESIGN: Prospective cohort study SETTING: Tertiary government hospital in Metro Manila STUDY POPULATION: Children on to 18 years old with pulmonary tuberculosis and normal liver function test at baseline. METHODS: Total bilirubin (TB), direct bilirubin (DB) and liver transaminases (AST and ALT) were checked routinely at baseline and at thow, four, eight and 12 weeks after starting treatment. Within the first month of treatment, blood was also taken for NAT2 genotyping. The identification of the three NAT2 polymorphisms that are associated with a slow acetylator status - 481C to T (NAT2*5), 950G to A (NAT2*6) and 857G to A (NAT2*7) was carried out by polymerase chain reaction-restriction fragment length polymorphism. All patients were followed up for a total of six months. The presense of any adverse effects like gastroinstestinal symptoms, rash, hepatitis or drug fever was also monitored. RESULTS: A total of 24 children [mean age: 5 years; 11 males] were included. Majority (96%) were diagnosed by passive detection and mean Z score was - 1.38 (1 to -3). No patient developed hepatotoxicity or any side effects to anti-TB drugs. In 23 patients who had NAT2 genotyping, 39% and 22% were alleles homozygous for the NAT2*6 and NAT2*7, respectively. There was a combination of alleles in only three (13%) subjects. CONCLUSION: NAT2*6 and NAT2*7 alleles associated with a slow acetylator status were detected among our patients although the presence of these variants did not lead to any hepatotoxicity nor any treatment-related side effects. A larger study with broader genotype analysis is needed to confirm the present findings.

Hepatotoxicidad por verapamil: reporte de un caso / Liver injury due to treatment with verapamil: case report

Drug induced liver injury is an infrequent adverse effect of Verapamil. It has been reported in about ten cases since 1981. We report a case of a middle-aged woman who received Verapamil in a dose of 120mg/d for eight weeks, developing a mixed hepatocellular and cholestatic pattern of liver injury without any symptoms. There was no evidence of eosinophilia. Liver function tests returned quickly to normal levels after discontinuation. As in previously reported cases, we hypothesize that this is an idiosyncratic mechanism of liver injury.

La hepatotoxicidad es un efecto adverso infrecuente de verapamil, existiendo alrededor de 10 casos reportados desde 1981. Relatamos el caso de una mujer de edad media que presenta una alteración de las pruebas hepáticas con patrón mixto asociado al uso de verapamil 120 mg/d por 8 semanas sin síntomas asociados, la cual responde rápidamente a la suspensión de este fármaco. Al igual que en casos reportados previamente, planteamos como mecanismo de injuria una hepatotoxicidad idiosincrática por este medicamento.

Gene Expression Profiling of 6-MP (6-mercaptopurine) in Liver

The KFDA (Korea Food & Drug Administration) has performed a collaborative toxicogenomics project since 2003. Its aim is to construct a toxicology database of 12 compounds administered to mice at initial phase. We chose 6-MP (6-mercaptopurine) which has been used in the treatment of childhood leukemia. It was administered at low (0.224 mg/kg) and at high (2.24 mg/kg) dose (5 mice per group) intraperitonealy to the postnatal 6 weeks mice, then the serum and liver were collected at the indicated time (6, 24 and 72 h) after scarification. Serum biochemical markers for liver toxicity were measured and histopathologic studies also were carried out. The gene expression profiling was carried out by using Applied Biosystems 1700 Full Genome Expression Mouse. By self-organization maps (SOM), we identified groups with unique gene expression patterns, some of them are supposed to be related to 6-MP induced toxicity, including lipid metabolism abnormality, inflammatory response, oxidative stress, ATP depletion and cell death. The potential toxic effects appearing as gene expression changes are dependent of the time of 6-MP but independent of the dosage of it. This study would contribute to establishment of international database as well as national one about hepatotoxicity.

Toxic Effect of Glufosinate-Ammonium on Liver of Rats / 环境与健康杂志

Objective To study the toxic effect of glufosinate-ammonium on the liver. Methods SD rats aged 6 weeks with weight of 140-160 g were randomly divided into four groups, 20 (10 males and 10 females) in each group. The rats were treated for three months by gavaging different doses of glufosinate-ammonium (0, 100, 250, 500 mg/kg bw) for the experimental group and 2% Tween-80 solution for the control group. All the rats were weighted once a week. The activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in the serum were determined at the end of the study. Liver weight was measured and liver index was calculated. Pathological examination was performed. Results Treated with high-dose of glufosinate-ammonium, a retarded growth of rats was seen, the activity of ALT, AST and ALP increased significantly in both male and female rats, the liver index increased significantly and pathological changes of the liver were also observed compared with the control. No significant changes were found in the rats treated with moderate and low dose compared with the control. Conclusion Glufosinate-ammonium may produce a toxic effect on the liver of rat when the exposed dose is more than 500 mg/kg.