Reactive Oxygen Species (ROS) and Liver Disease Therapy

Bellanti, Francesco; Sastre, Juan; Serviddio, Gaetano

doi:10.1007/978-3-642-30018-9_141

Cited by 2 publications

(1 citation statement)

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“…Lower baseline hepatic GSH levels are also likely to render these mice more susceptible to other hepatotoxic stimuli (in addition to APAP), as well as to diseases in which lower GSH levels are known to be causative of disease progression. For example non-alcohol fatty liver disease, fibrosis, hepatocellular carcinoma, hepatitis and cirrhosis have all been linked with decreased antioxidant capacity [5] . In addition, hepatic GSH represents the major systemic store which can be mobilised as required to supply other physiological systems [25] .…”

Section: Discussionmentioning

confidence: 99%

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

Murray

Dong

Sawyer

et al. 2015

Free Radical Biology and Medicine

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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.

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Section: Discussionmentioning

confidence: 99%