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Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation.

ABSTRACT: The aim of the study was to investigate the protective effect of isoniazid-curcumin conjugate (INH-CRM) in INH-induced hepatic injury by biochemical analysis and histology examination of liver in Wistar rats. The biochemical analysis included determination of the levels of plasma cholesterol, triglycerides (TG), albumin content, and lipid peroxidation (MDA). INH-CRM administration resulted in a significant decrease in plasma cholesterol, TG, and MDA levels in the liver tissue homogenate with an elevation in albumin level indicating its hepatoprotective activity. Histology of the liver further confirmed the reduction in hepatic injury. The hepatoprotective with INH-CRM can be attributed to the antioxidant activity of curcumin. The conjugate probably stabilizes the curcumin molecule, preventing its presystemic metabolism thereby enhancing its bioavailability and therefore, its hepatoprotective activity. Thus, the novel INH-CRM has the potential to alleviate INH-induced liver toxicity in antitubercular treatment.

SUBMITTER: Singh C

PROVIDER: S-EPMC5598226 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation.

Singh Charan C Jodave Laxmikant L Bhatt Tara Datt TD Gill Manjinder Singh MS Suresh Sarasija S

Toxicology reports 20141016

The aim of the study was to investigate the protective effect of isoniazid-curcumin conjugate (INH-CRM) in INH-induced hepatic injury by biochemical analysis and histology examination of liver in Wistar rats. The biochemical analysis included determination of the levels of plasma cholesterol, triglycerides (TG), albumin content, and lipid peroxidation (MDA). INH-CRM administration resulted in a significant decrease in plasma cholesterol, TG, and MDA levels in the liver tissue homogenate with an ...[more]

PMID: 28962300

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Project description:IntroductionThe liver, the most important metabolic organ of the body, performs a wide variety of vital functions. Hepatic cell injury occurs by the activation of reactive oxygen species (ROS) that are generated by carbon tetrachloride (CCl4), xenobiotics, and other toxic substances through cytochrome P450-dependent steps resulting from the covalent bond formation with lipoproteins and nucleic acids. Observing the urgent state of hepatotoxic patients worldwide, different medicinal plants and their properties can be explored to combat such free radical damage to the liver. In vivo and in silico studies were designed and conducted to evaluate the antioxidant and hepatoprotective properties of Gynura procumbens in rats.Materials and methodsGynura procumbens leaves were collected and extracted using 70% ethanol. The required chemicals CCl4, standard drug (silymarin), and blood serum analysis kits were stocked. The in vivo tests were performed in 140 healthy Wister albino rats of either sex under well-controlled parameters divided into 14 groups, strictly maintaining Institutional Animal Ethics Committee (IEAC) protocols. For the histopathology study, 10% buffered neutral formalin was used for organ preservation. Later the specimens were studied under a fluorescence microscope. In silico molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies were performed, and the results were analyzed statistically.Results and discussionGynura procumbens partially negate the deleterious effect of carbon tetrachloride on normal weight gain in rats. The elevated level of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), creatinine, LDH, total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG), malondialdehyde (MDA), deoxyribonucleic acid (DNA) fragmentation ranges, gamma-glutamyl transferase (γ-GT) in CCl4 treated groups were decreased by both standard drug silymarin and G. procumbens leaf extract. We have found significant & highly significant changes statistically for different doses, here p<0.05 & p<0.01, respectively. On the other hand, G. procumbens and silymarin displayed Statistically significant (p<0.05) and high significant(p<0.01) increased levels of HDL, CAT SOD (here p<0.05 & p<0.01 for different doses) when the treatment groups were compared with the disease control group. Because the therapeutic activity imparted by plants and drugs accelerates the movement of the disturbed pathophysiological state toward the healthy state. In the molecular docking analysis, G. procumbens phytoconstituents performed poorly against transforming growth factor-beta 1 (TGF-β1) compared to the control drug silymarin. In contrast, 26 phytoconstituents scored better than the control bezafibrate against peroxisome proliferator-activated receptor alpha (PPAR-α). The top scoring compounds for both macromolecules were observed to form stable complexes in the molecular dynamics simulations. Flavonoids and phenolic compounds performed better than other constituents in providing hepatoprotective activity. It can, thus, be inferred that the extract of G. procumbens showed good hepatoprotective properties in rats.

Project description:Background:Liver is a vital organ that plays a major role in the elimination of xenobiotics from the body. Diseases that affect the liver become major health problems and challenge health-care professionals as well as the pharmaceutical industry. Since the conventional treatment of liver diseases is associated with a wide range of adverse effects, botanical agents are commonly used. Among these agents, Clutia abyssinica is the most widely used herb in Ethiopian traditional medicine. Objective:To evaluate the hepatoprotective activity of the crude 80% methanol extract and solvent fractions of Clutia abyssinica leaves in mice. Methods:The leaves of Clutia abyssinica were extracted by cold maceration using 80% methanol as a solvent, and the solvent fractions were obtained in liquid-liquid extraction with chloroform, n-butanol and distilled water. Male mice were treated with the vehicles (distilled water or 2% Tween 80), three different doses (100, 200 and 400 mg/kg) of the crude 80% methanol extract and three solvent fractions, the standard drug (silymarin 100 mg/kg), and the hepatotoxicant carbon tetrachloride (CCl4). Then, the levels of biomarkers of liver injury - such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) - and liver function such as total protein, albumin, and bilirubin were measured. Evaluation of the change in body weight and liver weight, histopathologic examination and in vitro antioxidant assay against CCl4-induced hepatotoxicity were also carried out. Results:The 80% methanol extract decreased the absolute and relative weight of the liver of mice at the doses of 200 and 400 mg/kg (p<0.01 and p<0.001, respectively). It also suppressed the plasma levels of AST, ALT and ALP (p<0.001) in the aforementioned doses. Among fractions, the n-butanol fraction showed maximum hepatoprotective activity in its dose of 200 and 400 mg/kg (p<0.001, in all cases). Likewise, the chloroform fraction (400 mg/kg) reduced to a similar extent (p<0.001 in all cases). In stark contrast, the aqueous fraction failed to affect the levels of all biomarkers of hepatocyte injury. The crude methanol extract and n-butanol fraction were able to return the normal hepatic architecture of hepatocytes and scavenge free radicals in the 1,1-diphenylpicrylhydrazyl (DPPH) assay. Conclusion:Clutia abyssinica is endowed with hepatoprotective activity, probably mediated via its antioxidant activity. Thus, Clutia abyssinica can be taken as one candidate for the development of hepatoprotective agents because of its good safety profile.

Dataset Information

Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation.

Publications

Hepatoprotective agent tethered isoniazid for the treatment of drug-induced hepatotoxicity: Synthesis, biochemical and histopathological evaluation.

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