Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes

Meeta Jaiswal, Nicholas F La Russo, Richard A. Shapiro, Timothy R. Billiar, Gregory James Gores

Research output: Contribution to journalArticle

151 Citations (Scopus)

Abstract

Background & Aims: Chronic inflammation, a risk factor for the development of bile duct cancer, induces inducible nitric oxide synthase (iNOS) with nitric oxide (NO) generation, which promotes oxidative damage of DNA, a process that probably is important in the initiation and progression of malignancies. Because inhibition of DNA repair is required for accumulation of oxidative DNA lesions, our aim was to determine if NO also inhibits repair of oxidative DNA damage. Methods: A cholangiocarcinoma cell line and a cholangiocyte cell line were transfected with iNOS. Results: Extracts from transfected but not untransfected cells were unable to repair 8-oxodeoxyguanine (8-oxodG); this effect was irreversible because addition of dithiothreitol to cell extracts had no effect. NO inhibition of 8-oxodG repair was blocked by NO scavengers but not by peroxynitrite scavengers or inhibitors of the soluble guanylyl cyclase/protein kinase G pathway. NO also potentiated hydrogen peroxide-induced DNA damage. Finally, immunohistochemistry in human liver samples uniformly demonstrated de novo expression of iNOS and the presence of 3-nitrotyrosine and 8-oxodG formation in the biliary epithelia of 30 patients with primary sclerosing cholangitis (a premalignant disease of the biliary tract) compared with controls. Conclusions: Collectively, these data implicate NO-mediated inhibition of 8-oxodG base excision DNA repair processes as a mechanism potentiating DNA damage in human inflammatory diseases involving the biliary tract.

Original languageEnglish (US)
Pages (from-to)190-199
Number of pages10
JournalGastroenterology
Volume120
Issue number1
StatePublished - 2001
Externally publishedYes

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DNA Repair
DNA Damage
Nitric Oxide
Nitric Oxide Synthase Type II
Biliary Tract Diseases
Bile Duct Neoplasms
Cyclic GMP-Dependent Protein Kinases
Cell Line
Sclerosing Cholangitis
Peroxynitrous Acid
Cholangiocarcinoma
Dithiothreitol
Cell Extracts
Hydrogen Peroxide
Epithelium
Immunohistochemistry
Inflammation
Liver
DNA
Neoplasms

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. / Jaiswal, Meeta; La Russo, Nicholas F; Shapiro, Richard A.; Billiar, Timothy R.; Gores, Gregory James.

In: Gastroenterology, Vol. 120, No. 1, 2001, p. 190-199.

Research output: Contribution to journalArticle

Jaiswal, Meeta ; La Russo, Nicholas F ; Shapiro, Richard A. ; Billiar, Timothy R. ; Gores, Gregory James. / Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. In: Gastroenterology. 2001 ; Vol. 120, No. 1. pp. 190-199.
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