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.
Subject(s)
Acetaminophen/adverse effects , Analgesics, Non-Narcotic/adverse effects , Betaine-Homocysteine S-Methyltransferase/genetics , Chemical and Drug Induced Liver Injury/genetics , Liver Failure, Acute/genetics , Vitamin U/metabolism , Acetaminophen/metabolism , Acetaminophen/pharmacokinetics , Animals , Betaine-Homocysteine S-Methyltransferase/metabolism , Chemical and Drug Induced Liver Injury/etiology , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/prevention & control , Diet , Gene Expression Profiling , Liver/metabolism , Liver/pathology , Liver Failure, Acute/chemically induced , Liver Failure, Acute/pathology , Liver Failure, Acute/prevention & control , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred Strains , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Sequence Analysis, DNAABSTRACT
Benzothiazine-substituted tetramic acids were discovered as highly potent non-nucleoside inhibitors of HCV NS5B polymerase. X-ray crystallography studies confirmed the binding mode of these inhibitors with HCV NS5B polymerase. Rational optimization of time dependent inactivation of CYP 3A4 and clearance was accomplished by incorporation of electron-withdrawing groups to the benzothiazine core.
