Department of Genetics and Genomics, Roche Palo Alto, Palo Alto, California 94304, USA.
Genome Res. 2010 Jan;20(1):28-35. doi: 10.1101/gr.097212.109. Epub 2009 Nov 18.
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.
对乙酰氨基酚诱导的肝毒性是急性肝衰竭和肝移植最常见的诱发原因，但当代医学实践主要集中在肝损伤发生后的患者管理上。使用多个近交系小鼠进行的综合遗传、转录和二维 NMR 代谢组学分析，以及对这些数据的基于知识的筛选，确定甜菜碱-同型半胱氨酸甲基转移酶 2（Bhmt2）是一种依赖于饮食的遗传因素，影响小鼠对乙酰氨基酚诱导的肝毒性的易感性。通过对蛋氨酸和谷胱甘肽生物合成的影响，Bhmt2 可以利用其底物（S-甲基甲硫氨酸[SMM]）在体内提供对乙酰氨基酚诱导损伤的保护作用。由于 SMM 仅在植物中合成，因此 Bhmt2 以依赖于饮食的方式发挥其有益作用。Bhmt2 的鉴定和受影响的生物合成途径表明，小鼠中综合基因组分析的新方法如何为一个主要的公共卫生问题提供独特且适用于临床的方法。
