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

作者：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

来源：Genome Research, 2010, 20(1): 28-35.

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.

• 出版日期2010-1
• 单位NIH