An integrative genomic analysis identifies Bhmt2 as a diet-dependent genetic factor protecting against acetaminophen-induced liver toxicity

• Published in: Genome research 2010-01, Vol.20 (1), p.28-35
• Main Authors: Liu, Hong-Hsing, Lu, Peng, Guo, Yingying, Farrell, Erin, Zhang, Xun, Zheng, Ming, Bosano, Betty, Zhang, Zhaomei, Allard, John, Liao, Guochun, Fu, Siyu, Chen, Jinzhi, Dolim, Kimberly, Kuroda, Ayako, Usuka, Jonathan, Cheng, Janet, Tao, William, Welch, Kevin, Liu, Yanzhou, Pease, Joseph, de Keczer, Steve A, Masjedizadeh, Mohammad, Hu, Jing-Shan, Weller, Paul, Garrow, Tim, Peltz, Gary
• Format: Article
• Language: English
• Subjects: Acetaminophen - adverse effects; Acetaminophen - metabolism; Acetaminophen - pharmacokinetics; Analgesics, Non-Narcotic - adverse effects; Animals; Betaine-Homocysteine S-Methyltransferase - genetics; Betaine-Homocysteine S-Methyltransferase - metabolism; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - pathology; Chemical and Drug Induced Liver Injury - prevention & control; Diet; Gene Expression Profiling; Letter; Liver - metabolism; Liver - pathology; Liver Failure, Acute - chemically induced; Liver Failure, Acute - genetics; 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, DNA; Vitamin U - metabolism
• ISSN: 1088-9051; 1549-5469
• DOI: 10.1101/gr.097212.109

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.