Expression Levels of GABA-A Receptor Subunit Alpha 3, Gabra3 and Lipoprotein Lipase, Lpl Are Associated with the Susceptibility to Acetaminophen-Induced Hepatotoxicity
Biomolecules & Therapeutics
; : 112-121, 2017.
Article
in English
| WPRIM (Western Pacific)
| ID: wpr-226871
Responsible library:
WPRO
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 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.
Full text:
Available
Database:
WPRIM (Western Pacific)
Main subject:
Genetic Variation
/
Incidence
/
Receptors, GABA-A
/
Toxicogenetics
/
Microarray Analysis
/
Chemical and Drug Induced Liver Injury
/
Real-Time Polymerase Chain Reaction
/
Transcriptome
/
Lipoprotein Lipase
/
Lipoproteins
Type of study:
Incidence study
/
Prognostic study
Limits:
Animals
Language:
English
Journal:
Biomolecules & Therapeutics
Year:
2017
Document type:
Article