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

Genome Res. 2010 Jan;20(1):28-35. doi: 10.1101/gr.097212.109. Epub 2009 Nov 18.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • 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*

Substances

  • Analgesics, Non-Narcotic
  • Vitamin U
  • Acetaminophen
  • Betaine-Homocysteine S-Methyltransferase

Associated data

  • GEO/GSE17649