Decreased nucleotide excision repair in steatotic livers associates with myeloperoxidase-immunoreactivity

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• 作者：Marten A. Schults ; Peter W. Nagle ; S ; er S. Rensen ; Roger W. Godschalk ; Armelle Munnia ; Marco Peluso ; S ; ra M. Claessen ; Jan W. Greve ; Ann Driessen ; Froukje J. Verdam ; Wim A. Buurman ; Frederik J. van Schooten ; Rol ; K. Chiu
• 关键词：¦ÃH2AX ; histone 2AX phosphorylation ; H2O2 ; hydrogen peroxide ; HCC ; hepatocellular carcinoma ; HOCl ; hypochlorous acid ; M1dG ; 3-(2-deoxy-¦Â-d-erythro-pentofuranosyl)pyrimido [1 ; 2-¦Á]purin-10(3H)-one ; MPO ; myeloperoxidase ; NAFLD ; nonalcoholic fatty liver dis
• 刊名：Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
• 出版年：2012
• 出版时间：1 August, 2012
• 年：2012
• 卷：736
• 期：1-2
• 页码：75-81
• 全文大小：778 K

文摘

Chronic inflammation is characterized by the influx of neutrophils and is associated with an increased production of reactive oxygen species that can damage DNA. Oxidative DNA damage is generally thought to be involved in the increased risk of cancer in inflamed tissues. We previously demonstrated that activated neutrophil mediated oxidative stress results in a reduction in nucleotide excision repair (NER) capacity, which could further enhance mutagenesis. Inflammation and oxidative stress are critical factors in the progression of nonalcoholic fatty liver disease that is linked with enhanced liver cancer risk. In this report, we therefore evaluated the role of neutrophils and the associated oxidative stress in damage recognition and DNA repair in steatotic livers of 35 severely obese subjects with either nonalcoholic steatohepatitis (NASH) (n = 17) or steatosis alone (n = 18). The neutrophilic influx in liver was assessed by myeloperoxidase (MPO) staining and the amount of oxidative DNA damage by measuring M₁dG adducts. No differences in M₁dG adduct levels were observed between patients with or without NASH and also not between individuals with high or low MPO immunoreactivity. However, we found that high expression of MPO in the liver, irrespective of disease status, reduced the damage recognition capacity as determined by staining for histone 2AX phosphorylation (¦ÃH2AX). This reduction in ¦ÃH2AX formation in individuals with high MPO immunoreactivity was paralleled by a significant decrease in NER capacity as assessed by a functional repair assay, and was not related to cell proliferation. Thus, the observed reduction in NER capacity upon hepatic inflammation is associated with and may be a consequence of reduced damage recognition. These findings suggest a novel mechanism of liver cancer development in patients with nonalcoholic fatty liver disease.