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

Liu, Hong-Hsing; Lü, 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 C.; Welch, Kevin D.; Liu, Yanzhou; Pease, Joseph; Keczer, Steve A. De; Masjedizadeh, Mohammad R.; Hu, Jing; Weller, Paul; Garrow, T.A.; Peltz, Gary

doi:10.1101/gr.097212.109

Cited by 45 publications

(44 citation statements)

References 47 publications

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“…In this study, hepatic expression of the following genes were determined after APAP administration: NF-E2-related factor-2 (Nrf2), heme oxygenase-1 (HO-1), heat shock protein 70 (Hsp70), insulin-like growth factor binding protein-1 (IGFBP-1), ␥-glutamylcysteine synthetase (␥GCS), Tribbles homolog 3 (Trib3), glutathione transferases (GSTs) -1 (GSTP1) and GST (GSTK), peroxisome proliferator-activated receptor-␣ (PPAR␣), L-carnitine palmitoyltransferase 1 (L-CPT1), acylcoenzyme A oxidase (ACO), and pyruvate dehydrogenase kinase 4 (PDK4). Recent investigations showed that increased Trib3 expression was a good marker to detect GSH depletion secondary to its conjugation (Gao et al, 2010), and high basal PDK4 expression could increase sensitivity to APAP-induced hepatotoxicity (Liu et al, 2010). As shown in Fig.…”

Section: Preliminary Investigations In Lean and Obese Micementioning

confidence: 98%

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Aubert

Begriche

Delannoy

et al. 2012

J Pharmacol Exp Ther

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Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The preexistence of fat accumulation and CYP2E1 induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob, and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared with ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ ob, and db/db mice, and investigations were carried out 0.5, 2, 4, and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-Jun N-terminal kinase activation, changes in gene expression, and mitochondrial DNA levels were not greater compared with the other genotypes. Furthermore, in the db/db genotype plasma lactate and ␤-hydroxybutyrate were not specifically altered, whereas the plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders.

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Section: Preliminary Investigations In Lean and Obese Micementioning

confidence: 98%

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Aubert

Begriche

Delannoy

et al. 2012

J Pharmacol Exp Ther

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“…In fact, analysis of mouse genetic models has generated novel approaches for treatment of narcotic drug addiction (20) and for prevention of acetaminophen-induced liver toxicity (21). Differences in response to RSV have been observed among inbred mouse strains, including differences in viral load (22)(23)(24) postinfection, and in eosinophilic responses after vaccination with the RSV glycoprotein (25,26).…”

Section: R Espiratory Syncytial Virus (Rsv) Is the Most Significant Cmentioning

confidence: 99%

Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent

Tregoning

Yamaguchi

Wang

et al. 2010

The Journal of Immunology

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Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2k, C3H/HeN) and sensitive (H-2b, BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC–dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection.

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“…We also evaluated a common nonsynonymous polymorphism in the human CD44 gene (I479T) that was associated with increased serum liver injury biomarker levels in healthy volunteers who chronically consumed acetaminophen (Watkins et al, 2006;Harrill et al, 2009), and also a common nonsynonymous polymorphism in the human betaine-homocysteine methyltransferase 1 (BHMT1) gene (R239Q) because the closely related murine Bhmt2 gene was previously identified as protective against acetaminopheninduced hepatotoxicity in a mouse genomics study (Liu et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

et al. 2013

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Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a singletime-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophenmetabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients.This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminopheninduced ALF.

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

Cited by 45 publications

References 47 publications

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

Genetic Susceptibility to the Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Is MHC Dependent

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

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