A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis.
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.
Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 ahharrill@uams.edu.
Rachel J
RJ
Church
Drug Safety Research and Development, Pfizer Global Research and Development, Groton, Connecticut 06340 ahharrill@uams.edu.
Hong
H
Wu
Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 ahharrill@uams.edu.
Merrie
M
Mosedale
Discovery Sciences, RTI International, Research Triangle Park, North Carolina 27709.
Susan J
SJ
Sumner
Discovery Sciences, RTI International, Research Triangle Park, North Carolina 27709.
Wimal
W
Pathmasiri
Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
Catherine L
CL
Kurtz
Drug Safety Research and Development, Pfizer Global Research and Development, Groton, Connecticut 06340.
Mathew T
MT
Pletcher
Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709.
John S
JS
Eaddy
Drug Safety Research and Development, Pfizer Global Research and Development, Groton, Connecticut 06340.
Karamjeet
K
Pandher
Janssen Research and Development, Drug Safety Sciences, Raritan, New Jersey 08869.
Monica
M
Singer
Janssen Research and Development, Drug Safety Sciences, Raritan, New Jersey 08869.
Ameesha
A
Batheja
Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
Paul B
PB
Watkins
Drug Safety Research and Development, Pfizer Global Research and Development, Groton, Connecticut 06340 ahharrill@uams.edu.
Karissa
K
Adkins
Hamner-University of North Carolina Institute for Drug Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina 27709 Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 The University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 ahharrill@uams.edu.
Alison H
AH
Harrill
D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects*; D002784:Cholesterol / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007538:Isoniazid / Q000009:adverse effects*; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D055432:Metabolomics; D051379:Mice; D008815:Mice, Inbred Strains; D000070780:Perilipin-2; D020641:Polymorphism, Single Nucleotide; D049490:Systems Biology
D000995:Antitubercular Agents; D008565:Membrane Proteins; D000070780:Perilipin-2; D002784:Cholesterol; D007538:Isoniazid