vitamin-u and Liver-Failure--Acute

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.

Topics: Acetaminophen; Analgesics, Non-Narcotic; Animals; Betaine-Homocysteine S-Methyltransferase; Chemical and Drug Induced Liver Injury; Diet; Gene Expression Profiling; Liver; Liver Failure, Acute; Magnetic Resonance Spectroscopy; Mice; Mice, Inbred Strains; Molecular Sequence Data; Oligonucleotide Array Sequence Analysis; Sequence Analysis, DNA; Vitamin U