This article [below] just came to my attention––largely because it won the “Toxicol Sci Best Paper” Award for 2o14.
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 response to this drug have remained elusive. A genetically diverse mouse population model, in combination with a systems-biology approach, was used to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals.
Following three days of oral INH, sensitive mouse strains developed severe microvesicular steatosis, compared with corresponding vehicle control-treated mice. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered by INH treatment. Genes associated with INH treatment and susceptibility to INH-caused hepatic steatosis included: apolipoprotein A-IV, lysosomal-associated membrane protein-1, and choline phosphotransferase-1. These alterations were accompanied by metabolomic changes––including decreased levels of glutathione and the choline metabolites, betaine and phosphocholine––suggesting that oxidative stress and diminished 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 individuals susceptible to INH-induced steatosis. Taken together, these data suggest that INH-induced steatosis is caused by not one, but multiple, events involving lipid retention in livers of genetically-sensitive individuals. This study also underscores the value of using a mouse diversity panel––to investigate clinically relevant diseases caused by environmental toxicants including drugs.
Church RJ, Wu H, Mosedale M, Sumner SJ, Pathmasiri W, Kurtz CL, Pletcher MT, Eaddy JS, Pandher K, Singer M, Batheja A, Watkins PB, Adkins K, and Harrill AH.
A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis.
Toxicol Sci 2o14; 140, 481-492.