RGD Reference Report - Knock down of gamma-glutamylcysteine synthetase in rat causes acetaminophen-induced hepatotoxicity. - Rat Genome Database

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Knock down of gamma-glutamylcysteine synthetase in rat causes acetaminophen-induced hepatotoxicity.

Authors: Akai, S  Hosomi, H  Minami, K  Tsuneyama, K  Katoh, M  Nakajima, M  Yokoi, T 
Citation: Akai S, etal., J Biol Chem. 2007 Aug 17;282(33):23996-4003. Epub 2007 Jun 15.
RGD ID: 10402383
Pubmed: PMID:17573345   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M702819200   (Journal Full-text)

Drug-induced hepatotoxicity is mainly caused by hepatic glutathione (GSH) depletion. In general, the activity of rodent glutathione S-transferase is 10 to 20 times higher than that of humans, which could make the prediction of drug-induced hepatotoxicity in human more difficult. Gamma-glutamylcysteine synthetase (gamma-GCS) mainly regulates de novo synthesis of GSH in mammalian cells and plays a central role in the antioxidant capacity of cells. In this study, we constructed a GSH-depletion experimental rat model for the prediction of human hepatotoxicity. An adenovirus vector with short hairpin RNA against rat gamma-GCS heavy chain subunit (GCSh) (AdGCSh-shRNA) was constructed and used to knock down the GCSh. In in vitro study in H4IIE cells, a rat hepatoma cell line, GCSh mRNA and protein were significantly decreased by 80% and GSH was significantly decreased by 50% 3 days after AdGCSh-shRNA infection. In the in vivo study in rat, the hepatic GSH level was decreased by 80% 14 days after a single dose of AdGCSh-shRNA (2 x 10(11) pfu/ml/body), and this depletion continued for at least 2 weeks. Using this GSH knockdown rat model, acetaminophen-induced hepatotoxicity was shown to be significantly potentiated compared with normal rats. This is the first report of a GSH knockdown rat model, which could be useful for highly sensitive tests of acute and subacute toxicity for drug candidates in preclinical drug development.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Chemical and Drug Induced Liver Injury  ISOGclc (Rattus norvegicus)10402383; 10402383 RGD 
Chemical and Drug Induced Liver Injury  IMP 10402383 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gclc  (glutamate-cysteine ligase, catalytic subunit)

Genes (Mus musculus)
Gclc  (glutamate-cysteine ligase, catalytic subunit)

Genes (Homo sapiens)
GCLC  (glutamate-cysteine ligase catalytic subunit)


Additional Information