An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity.
Genome Res
; 20(1): 28-35, 2010 Jan.
Article
de En
| MEDLINE
| ID: mdl-19923254
ABSTRACT
Acetaminophen-induced liver toxicity is the most frequent precipitating cause of acute liver failure and liver transplant, but contemporary medical practice has mainly focused on patient management after a liver injury has been induced. An integrative genetic, transcriptional, and two-dimensional NMR-based metabolomic analysis performed using multiple inbred mouse strains, along with knowledge-based filtering of these data, identified betaine-homocysteine methyltransferase 2 (Bhmt2) as a diet-dependent genetic factor that affected susceptibility to acetaminophen-induced liver toxicity in mice. Through an effect on methionine and glutathione biosynthesis, Bhmt2 could utilize its substrate (S-methylmethionine [SMM]) to confer protection against acetaminophen-induced injury in vivo. Since SMM is only synthesized in plants, Bhmt2 exerts its beneficial effect in a diet-dependent manner. Identification of Bhmt2 and the affected biosynthetic pathway demonstrates how a novel method of integrative genomic analysis in mice can provide a unique and clinically applicable approach to a major public health problem.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Vitamine U
/
Défaillance hépatique aigüe
/
Analgésiques non narcotiques
/
Betaine-homocysteine S-methyltransferase
/
Lésions hépatiques dues aux substances
/
Acétaminophène
Type d'étude:
Etiology_studies
/
Prognostic_studies
Limites:
Animals
Langue:
En
Journal:
Genome Res
Sujet du journal:
BIOLOGIA MOLECULAR
/
GENETICA
Année:
2010
Type de document:
Article
Pays d'affiliation:
États-Unis d'Amérique