ArticleToxicological sciences : an official journal of the Society of Toxicology2014
A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 54 citations in OpenAlex.
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- Natural variation suggests candidate genes underlyingbioRxiv : the preprint server for biology · 2025Article
- Preserving mitochondrial homeostasis protects against drug-induced liver injury via inducing OPTN (optineurin)-dependent Mitophagy.Autophagy · 2024Article
- Lansoprazole Ameliorates Isoniazid-Induced Liver Injury.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Model systems and organisms for addressing inter- and intra-species variability in risk assessment.Regulatory toxicology and pharmacology : RTP · 2022Review
- Drug delivery systems for RNA therapeutics.Nature reviews. Genetics · 2022Review
- Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction.Acta pharmaceutica Sinica. B · 2021Review
- Association of Cesarean Delivery and Formula Supplementation with the Stool Metabolome of 6-Week-Old Infants.Metabolites · 2021Article
- Human-relevant mechanisms and risk factors for TAK-875-Induced liver injury identified via a gene pathway-based approach in Collaborative Cross mice.Toxicology · 2021Article
- SSMD: a semi-supervised approach for a robust cell type identification and deconvolution of mouse transcriptomics data.Briefings in bioinformatics · 2021Article
- Clinical perspectives of isoniazid-induced liver injury.Liver research (Beijing, China) · 2021Review
- Identification of Candidate Risk Factor Genes for Human Idelalisib Toxicity Using a Collaborative Cross Approach.Toxicological sciences : an official journal of the Society of Toxicology · 2019Article
- Deficiency of N-acetyltransferase increases the interactions of isoniazid with endobiotics in mouse liver.Biochemical pharmacology · 2017Article
- Genetic determinants of susceptibility to silver nanoparticle-induced acute lung inflammation in mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2017Article
- Pretreatment with indomethacin results in increased heat stroke severity during recovery in a rodent model of heat stroke.Journal of applied physiology (Bethesda, Md. : 1985) · 2017Article
- New Rodent Population Models May Inform Human Health Risk Assessment and Identification of Genetic Susceptibility to Environmental Exposures.Environmental health perspectives · 2017Review
- Metabolomics reveal physiological changes in mayfly larvae (Neocloeon triangulifer) at ecological upper thermal limits.Journal of insect physiology · 2017Article
- Disposition of intravenously or orally administered silver nanoparticles in pregnant rats and the effect on the biochemical profile in urine.Journal of applied toxicology : JAT · 2017Article
- Article
- Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure.Environmental science & technology · 2017Article
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been associated with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in the response to this drug have remained elusive. A genetically diverse mouse population model in combination with a systems biology approach was utilized to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals. Sensitive mouse strains developed severe microvesicular steatosis compared with corresponding vehicle control mice following 3 days of oral treatment with INH. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered with INH treatment. Those associated with INH treatment and susceptibility to INH-induced steatosis in the liver included apolipoprotein A-IV, lysosomal-associated membrane protein 1, and choline phosphotransferase 1. These alterations were accompanied by metabolomic changes including reduced levels of glutathione and the choline metabolites betaine and phosphocholine, suggesting that oxidative stress and reduced lipid export may additionally contribute to INH-induced steatosis. Finally, genome-wide association mapping revealed that polymorphisms in perilipin 2 were linked to increased triglyceride levels following INH treatment, implicating a role for inter-individual differences in lipid packaging in the susceptibility to INH-induced steatosis. Taken together, our data suggest that INH-induced steatosis is caused by not one, but multiple events involving lipid retention in the livers of genetically sensitive individuals. This work also highlights the value of using a mouse diversity panel to investigate drug-induced responses across a diverse population.
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