Biomol Ther (Seoul)  
Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity
Minjeong Kim1,†, Jun-Won Yun2,†, Kyeho Shin3, Yejin Cho4, Mijeong Yang4, Ki Taek Nam4,* and Kyung-Min Lim1,*
1College of Pharmacy, Ewha Womans University, Seoul 03760,
2Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080,
3Department of Beauty Coordination, Suwon Science College, Suwon 18516,
4Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
E-mail: kmlim@ewha.ac.kr (Lim KM), kitaek@yuhs.ac (Nam KT)
Tel: +82-2-3277-3055 (Lim KM), +82-2-2228-0754 (Nam KT)
Fax: +82-2-3277-3760 (Lim KM), +82-2-2227-8129 (Nam KT)
The first two authors contributed equally to this work.
Received: April 5, 2016; Revised: May 9, 2016; Accepted: May 11, 2016; Published online: August 19, 2016.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Drug-induced liver injury (DILI) is the serious and fatal drug-associated adverse effect, but its incidence is very low and individual variation in severity is substantial. Acetaminophen (APAP)-induced liver injury accounts for >50% of reported DILI cases but little is known for the cause of individual variations in the severity. Intrinsic genetic variation is considered a key element but the identity of the genes was not well-established. Here, pre-biopsy method and microarray technique was applied to uncover the key genes for APAP-induced liver injury in mice, and a cause and effect experiment employing quantitative real-time PCR was conducted to confirm the correlation between the uncovered genes and APAP-induced hepatotoxicity. We identified the innately and differentially expressed genes of mice susceptible to APAP-induced hepatotoxicity in the pre-biopsied liver tissue before APAP treatment through microarray analysis of the global gene expression profiles (Affymetrix GeneChip? Mouse Gene 1.0 ST for 28,853 genes). Expression of 16 genes including Gdap10, Lpl, Gabra3 and Ccrn4l were significantly different (t-test: FDR <10%) more than 1.5 fold in the susceptible animals than resistant. To confirm the association with the susceptibility to APAP-induced hepatotoxicity, another set of animals were measured for the expression level of selected 4 genes (higher two and lower two genes) in the liver pre-biopsy and their sensitivity to APAP-induced hepatotoxicity was evaluated post hoc. Notably, the expressions of Gabra3 and Lpl were significantly correlated with the severity of liver injury (p<0.05) demonstrating that these genes may be linked to the susceptibility to APAP-induced hepatotoxicity.
Keywords: Acetaminophen, Hepatotoxicity, Toxicogenomics, GABA-A receptor subunit alpha 3, Lipoprotein lipase


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