NADPH oxidase 4 regulates homocysteine metabolism and protects against acetaminophen-induced liver damage in mice

Autor: Anna Caldwell, Ralf P. Brandes, John M. Halket, Alison C. Brewer, Tracy Dew, Roy Sherwood, Katrin Schröder, Ajay M. Shah, Thomas V.A. Murray, Daniel Martin, Alberto Quaglia, Rajesh K. Mistry, Robin D. Hughes, Xuebin Dong, Greta J. Sawyer, Narayana Anilkumar, Simon Burr
Rok vydání: 2015
Předmět:
S-Adenosylmethionine
Homocysteine
Transsulfuration
Transsulfuration pathway
Biochemistry
Immunoenzyme Techniques
Mice
chemistry.chemical_compound
AST
aspartate-transaminase
Methionine
APAP
acetaminophen (paracetamol)
MS
methionine synthase
BHMT
betaine-homocysteine methyltransferase
GSH
Glutathione
Hcy
Homocysteine
Cells
Cultured
Mice
Knockout
chemistry.chemical_classification
NADPH oxidase
Betaine-homocysteine-methyltransferase (BHMT)
Liver Diseases
NOX4
Original Contribution
Hep G2 Cells
SNP
single nucleotide polymorphism
Analgesics
Non-Narcotic
Glutathione
Nox4
NADPH Oxidase 4
Liver
NADPH Oxidase 4
ALT
alanine-transaminase
Female
Blotting
Western
Biology
RNS
reactive nitrogen species
Nox4
ROS
reactive oxygen species
Physiology (medical)
NADQI
N-acetly-p-benzoquinone imine
BIAM
N-(biotinoyl)-N'-(iodoacetyl)ethylenediamine
Animals
Humans
Cysteine
Redox-signaling
Wt
wild-type
Acetaminophen
Reactive oxygen species
CBS
cysthathionine β-synthase
GSSG
oxidised glutathione
Hepatotoxicity
NADPH Oxidases
GWAS
genome-wide association analysis
GCL
γ-glutamylcysteine ligase
CGL
cystathionine γ-lyase
Betaine
chemistry
GS
glutathione synthetase
NAC
N-acetyl cysteine
biology.protein
DMG
dimethylglycine
Reactive Oxygen Species
Zdroj: Free Radical Biology & Medicine
ISSN: 0891-5849
DOI: 10.1016/j.freeradbiomed.2015.09.015
Popis: Glutathione is the major intracellular redox buffer in the liver and is critical for hepatic detoxification of xenobiotics and other environmental toxins. Hepatic glutathione is also a major systemic store for other organs and thus impacts on pathologies such as Alzheimer's disease, Sickle Cell Anaemia and chronic diseases associated with aging. Glutathione levels are determined in part by the availability of cysteine, generated from homocysteine through the transsulfuration pathway. The partitioning of homocysteine between remethylation and transsulfuration pathways is known to be subject to redox-dependent regulation, but the underlying mechanisms are not known. An association between plasma Hcy and a single nucleotide polymorphism within the NADPH oxidase 4 locus led us to investigate the involvement of this reactive oxygen species- generating enzyme in homocysteine metabolism. Here we demonstrate that NADPH oxidase 4 ablation in mice results in increased flux of homocysteine through the betaine-dependent remethylation pathway to methionine, catalysed by betaine-homocysteine-methyltransferase within the liver. As a consequence NADPH oxidase 4-null mice display significantly lowered plasma homocysteine and the flux of homocysteine through the transsulfuration pathway is reduced, resulting in lower hepatic cysteine and glutathione levels. Mice deficient in NADPH oxidase 4 had markedly increased susceptibility to acetaminophen-induced hepatic injury which could be corrected by administration of N-acetyl cysteine. We thus conclude that under physiological conditions, NADPH oxidase 4-derived reactive oxygen species is a regulator of the partitioning of the metabolic flux of homocysteine, which impacts upon hepatic cysteine and glutathione levels and thereby upon defence against environmental toxins.
Highlights • Ablation of Nox4 results in lowered plasma homocysteine levels in mice. • This results from increased folate-independent remethylation of homocysteine. • As a consequence mice display reduced hepatic cysteine and glutathione. • Reduced glutathione levels render the mice susceptible to hepatotoxic agents. • Nox4 is a physiological regulator of partitioning of homocysteine metabolic flux.
Databáze: OpenAIRE
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