Isoniazid-induced hepatotoxicity and neurotoxicity in rats investigated by 1H NMR based metabolomics approach.

Isoniazid (INH) is a well-known therapeutic and preventive agent against tuberculosis. However, high rates of side effects with various symptoms concerning hepatotoxicity and neurotoxicity have been reported, hindering its wide and safe application in clinic. In this investigation, rats were intoxicated with INH by gavage at doses of 200 and 400 mg/kg for 7 consecutive days to develop a rat model of acute INH-induced toxicity, which was investigated by a 1H NMR-based metabolomics complemented with clinical assays, histopathological inspection and western blotting. INH decreased the weights of dosed rats and induced seizure and hepatic steatosis dose-dependently. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of the NMR profiles of rat livers, brains and serum revealed that INH dose-dependently induced oxidative stress, disorders of excitatory and inhibitory amino acid neurotransmitters, and disturbances of energy metabolism and osmotic balance, which could help clarify the mechanisms of INH-induced hepatotoxicity and neurotoxicity. This integrated metabolomics approach showcased its ability to characterize the global metabolic status of organism, providing a powerful and feasible tool to probe drug induced toxicity or side effects.

• Publication year

  2018

• Venue

  Toxicology Letters

• Publication date

  2018-10-01

• Fields of study

  Medicine, Chemistry

• Identifiers
  DOI 10.1016/j.toxlet.2018.05.032PMID 29936297
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Triheptanoin for the treatment of brain energy deficit: A 14‐year experience

  2017cited by this paper
• Pyrazinamide-induced hepatotoxicity and gender differences in rats as revealed by a 1H NMR based metabolomics approach.

  2017cited by this paper
• In vitro seizure like events and changes in ionic concentration.

  2016cited by this paper
• Potential of creatine or phosphocreatine supplementation in cerebrovascular disease and in ischemic heart disease

  2016cited by this paper
• Multi-tissue metabolic responses of goldfish (Carassius auratus) exposed to glyphosate-based herbicide.

  2016cited by this paper
• (1)H NMR metabolomics to study the effects of diazepam on anisatin induced convulsive seizures.

  2016cited by this paper
• Dietary interventions designed to protect the perinatal brain from hypoxic-ischemic encephalopathy--Creatine prophylaxis and the need for multi-organ protection.

  2016cited by this paper
• Mitochondrial oxidative stress and dysfunction induced by isoniazid: study on isolated rat liver and brain mitochondria

  2016cited by this paper
• Neuroprotective effects of a glutathione depletor in rat post-ischemic reperfusion brain damage.

  2015cited by this paper
• (1)H NMR based metabolomics approach to study the toxic effects of dichlorvos on goldfish (Carassius auratus).

  2015cited by this paper
• Insight into biological system responses in goldfish (Carassius auratus) to multiple doses of avermectin exposure by integrated 1H NMR-based metabolomics

  2015cited by this paper
• Crystal structure of the enoyl-ACP reductase of Mycobacterium tuberculosis (InhA) in the apo-form and in complex with the active metabolite of isoniazid pre-formed by a biomimetic approach.

  2015cited by this paper
• NMR-based metabolomics approach to study the toxicity of lambda-cyhalothrin to goldfish (Carassius auratus).

  2014cited by this paper
• Expanding the Limits of Human Blood Metabolite Quantitation Using NMR Spectroscopy

  2014cited by this paper
• A bird's eye view of anisatin induced convulsive seizures in brain by a (1)H NMR based metabolic approach.

  2014cited by this paper
• Direct Oxidation and Covalent Binding of Isoniazid to Rodent Liver and Human Hepatic Microsomes: Humans Are More Like Mice than Rats

  2012cited by this paper
• Metabolomics of cerebrospinal fluid reveals changes in the central nervous system metabolism in a rat model of multiple sclerosis

  2011cited by this paper
• GC‐MS‐based metabolomics reveals mechanism of action for hydrazine induced hepatotoxicity in rats

  2011cited by this paper
• Metabolomic analysis reveals novel isoniazid metabolites and hydrazones in human urine.

  2011cited by this paper
• Structuring and extracting knowledge for the support of hypothesis generation in molecular biology

  2009cited by this paper
• Metabolomics: A Global Biochemical Approach to the Study of Central Nervous System Diseases

  2009cited by this paper
• Intracellular Organic Osmolytes: Function and Regulation*

  2008cited by this paper
• WGCNA: an R package for weighted correlation network analysis

  2008cited by this paper
• Roles of the cation–chloride cotransporters in neurological disease

  2008cited by this paper
• Genetic polymorphisms of NAT2 and CYP2E1 associated with antituberculosis drug-induced hepatotoxicity in Korean patients with pulmonary tuberculosis.

  2007cited by this paper
• Adverse reactions to first-line antituberculosis drugs

  2006cited by this paper
• Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis.

  2005cited by this paper
• Defective N-acetylaspartate catabolism reduces brain acetate levels and myelin lipid synthesis in Canavan's disease.

  2005cited by this paper
• Seizures, Metabolic Acidosis and Coma Resulting from Acute Isoniazid Intoxication

  2005cited by this paper
• The potential of metabonomics in drug safety and toxicology.

  2004cited by this paper
• Global tuberculosis control: surveillance planning financing. WHO report 2003.

  2003cited by this paper
• Lactate efflux and the neuroenergetic basis of brain function

  2001cited by this paper
• Acceleration of phosphatidylcholine synthesis and breakdown by inhibitors of mitochondrial function in neuronal cells: a model of the membrane defect of Alzheimer's disease.

  2000cited by this paper
• Acute isoniazid intoxication: seizures, acidosis and coma.

  1999cited by this paper
• Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy

  1999cited by this paper
• Chemical Similarity Searching

  1998cited by this paper
• N-acetylaspartate in neuropsychiatric disorders.

  1995cited by this paper
• Investigation into the Role of N‐Acetylaspartate in Cerebral Osmoregulation

  1995cited by this paper
• Heme oxygenase-1 is associated with the neurofibrillary pathology of Alzheimer's disease.

  1994cited by this paper
• Convulsions induced by lindane and the involvement of the GABAergic system.

  1983cited by this paper
• Elevation of Brain GABA Content by Chronic Low‐Dosage Administration of Hydrazine, a Metabolite of Isoniazid

  1981cited by this paper
• GABA and seizures induced by inhibitors of glutamic acid decarboxylase

  1980cited by this paper
• An evaluation of the Coomassie brillant blue G-250 dye-binding method for quantitative protein determination.

  1977cited by this paper
• On the pattern of change in peripheral nerves produced by isoniazid intoxication in rats

  1967cited by this paper
• ISONIAZID-INDUCED ENCEPHALOPATHY.

  1965cited by this paper
• ISONIAZID-INDUCED ENCEPHALOPATHY.

  1965cited by this paper

• Molecular modelling assisted identification of novel Benzoxazole derivatives as hit molecules targeting Mycobacterial Membrane Protein Large 3 (MmpL3).

  2026cites this paper
• Investigation of the hepatoprotective potential of the hydroalcoholic leaves extract of Ricinus communis on isoniazid induced and thioacetamide induced hepatotoxicity in Wistar rats

  2025cites this paper
• Lansoprazole Ameliorates Isoniazid-Induced Liver Injury.

  2024cites this paper
• Which fluoroquinolone is safer when combined with bedaquiline for tuberculosis treatment: evidence from FDA Adverse Event Reporting System database from 2013 to 2024

  2024cites this paper
• Potential of Rambutan-Honey Antioxidants in Reducing Malondialdehyde Levels and Regenerating Hepatocyte Cells in Isoniazid-Rats Induced

  2024cites this paper
• Total cucurbitacins from Herpetospermum pedunculosum pericarp do better than Hu-lu-su-pian (HLSP) in its safety and hepatoprotective efficacy

  2024cites this paper
• Scopoletin a potential phytochemical therapy for antitubercular treatment drug induced liver injury (ATT-DILI) model in Wistar rats

  2023cites this paper
• Hepatoprotective potential of Phyllanthus niruri and Andrographis paniculata in isoniazid-rifampicin induced hepatotoxicity in rats.

  2023cites this paper
• Pharmacokinetic assessment of rifampicin and des-acetyl rifampicin in carbon tetrachloride induced liver injury model in Wistar rats

  2023cites this paper
• Drug-induced liver injury and anti-hepatotoxic effect of herbal compounds: a metabolic mechanism perspective.

  2023cites this paper
• The identification of key metabolites and mechanisms during isoniazid/rifampicin-induced neurotoxicity and hepatotoxicity in a mouse model by HPLC-TOF/MS-based untargeted urine metabolomics.

  2023cites this paper
• Metabolomic analyses redefine the biological classification of pancreatic cancer and correlate with clinical outcomes

  2022cites this paper
• Ferric oxide nanoparticles administration suppresses isoniazid induced oxidative stress in the rat brain tissue

  2022cites this paper
• Plasma metabolomic and lipidomic alterations associated with anti-tuberculosis drug-induced liver injury

  2022cites this paper
• Integration of metabolomics and proteomics analysis to explore the mechanism of neurotoxicity induced by receipt of isoniazid and rifampicin in mice.

  2022cites this paper
• Urine metabolomics and microbiome analyses reveal the mechanism of anti-tuberculosis drug-induced liver injury, as assessed for causality using the updated RUCAM: A prospective study

  2022cites this paper
• Acute hepatotoxicity and nephrotoxicity risk assessment of the Tibetan medicine 25 flavors of the turquoise pill based on 1H-NMR metabonomics.

  2021cites this paper
• Gut microbiota protects from triptolide-induced hepatotoxicity: key role of propionate and its downstream signalling events.

  2020cites this paper
• Toxicological Risks of Renqingchangjue in Rats Evaluated by 1H NMR-Based Serum and Urine Metabolomics Analysis

  2020cites this paper
• Involvement of dopamine signaling pathway in neurodevelopmental toxicity induced by isoniazid in zebrafish.

  2020cites this paper
• Neuroprotective effect of chrysin on isoniazid-induced neurotoxicity via suppression of oxidative stress, inflammation and apoptosis in rats.

  2020cites this paper
• Ratlarda İzoniazid Kaynaklı Akciğer Hasarına Karşı Krisinin Etkileri

  2020cites this paper
• Chemotherapeutic efficacy of cucurmosin for pancreatic cancer as an alternative of gemcitabine: a comparative metabolomic study.

  2020cites this paper
• Toxins mechanism in instigating hepatotoxicity

  2020cites this paper
• NMR as a “Gold Standard” Method in Drug Design and Discovery

  2020cites this paper
• Urine metabolomic responses to aerobic and resistance training in rats under chronic unpredictable mild stress

  2020cites this paper
• Metabolomics describes previously unknown toxicity mechanisms of isoniazid and rifampicin.

  2020cites this paper
• MCR-ALS analysis of 1H NMR spectra by segments to study the zebrafish exposure to acrylamide

  2020cites this paper
• Neurological and Psychiatric Side Effects of Antimicrobials

  2020cites this paper
• Effects of Chrysin Against Isoniazid-Induced Lung Injury in Rats

  2020cites this paper
• Clinical Aspects and Principles of Management of Tuberculosis

  2019influential citation