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Expression levels of GABA-A receptor subunit alpha 3, Gabra3 and lipoprotein lipase, Lpl are associated with the susceptibility to acetaminophen-induced hepatotoxicity
- Expression levels of GABA-A receptor subunit alpha 3, Gabra3 and lipoprotein lipase, Lpl are associated with the susceptibility to acetaminophen-induced hepatotoxicity
- Kim M.; Yun J.-W.; Shin K.; Cho Y.; Yang M.; Nam K.T.; Lim K.-M.
- Ewha Authors
- SCOPUS Author ID
- Issue Date
- Journal Title
- Biomolecules and Therapeutics
- Biomolecules and Therapeutics vol. 25, no. 2, pp. 112 - 121
- Acetaminophen; GABA-A receptor subunit alpha 3; Hepatotoxicity; Lipoprotein lipase; Toxicogenomics
- Korean Society of Applied Pharmacology
- SCIE; SCOPUS; KCI
- Document Type
- 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 by 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. © 2017 The Korean Society of Applied Pharmacology.
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