title: Expression Levels of GABA-A Receptor Subunit Alpha 3,Gabra3and Lipoprotein Lipase,LplAre Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity.
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 includingGdap10, Lpl, Gabra3andCcrn4lwere 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 bypost hoc. Notably, the expressions ofGabra3andLplwere 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.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Minjeong
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Experimental Animal Research, Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: Department of Beauty Coordination, Suwon Science College, Suwon 18516, Republic of Korea.
authors.forename: Kyeho
authors.initials: K
authors.lastname: Shin
authors.affiliation: Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Yejin
authors.initials: Y
authors.lastname: Cho
authors.affiliation: Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Mijeong
authors.initials: M
authors.lastname: Yang
authors.affiliation: Severance Biomedical Science Institute, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 03760, Republic of Korea.
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
keywords: Acetaminophen; GABA-A receptor subunit alpha 3; Hepatotoxicity; Lipoprotein lipase; Toxicogenomics