Inflammatory cytokines suppress arylamine N-acetyltransferase 1 in cholangiocarcinoma cells

World J Gastroenterol. 2007 Dec 14;13(46):6219-25. doi: 10.3748/wjg.v13.i46.6219.

Abstract

Aim: To evaluate the effect of inflammatory cytokines on arylamine N-acetyltransferase 1 (NAT1), which is a phase-II enzyme involved in the biotransformation of aromatic and heterocyclic amines found in food, drugs and the environment.

Methods: Human cholangiocarcinoma KKU-100 cells were treated with a mixture of proinflammatory cytokines (interferon-gamma, interleukin-1 beta and tumor necrosis factor-alpha) for 48 h, and the effect on NAT1 activity was assessed by high performance liquid chromatography, while NAT1 expression was determined by reverse-transcription polymerase chain reaction. The oxidative stress on the cells was examined by the formation of nitric oxide, superoxide anion and glutathione (GSH) levels. The cells were also treated with S-nitroso-glutathione (GSNO), a nitric oxide donor, to see if the responses were similar to those obtained with the inflammatory cytokines.

Results: Cytokines suppressed NAT1 activity, reducing the Vmax without affecting the Km. Cytokines also had a significant impact on the induction of nitric oxide production and in reducing the redox ratios of glutathione (GSH) and GSH disulfide. Treatment with GSNO for 2-48 h reduced NAT1 activity without affecting the GSH ratio. Moreover, inflammatory cytokines and GSNO suppressed NAT1 mRNA expression.

Conclusion: These findings indicate an association between inflammation and suppression of NAT1, which perhaps contributes to chemical-mediated toxicity and carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arylamine N-Acetyltransferase / metabolism*
  • Bile Duct Neoplasms / enzymology*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic*
  • Cell Line, Tumor
  • Cholangiocarcinoma / enzymology*
  • Cholangiocarcinoma / pathology
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Epithelial Cells / pathology
  • Glutathione / metabolism
  • Humans
  • Interferon-gamma / physiology*
  • Interleukin-1beta / physiology*
  • Isoenzymes / metabolism*
  • Nitric Oxide / metabolism
  • Nitric Oxide Donors / pharmacology
  • Oxidation-Reduction
  • Oxidative Stress
  • RNA, Messenger / metabolism
  • S-Nitrosoglutathione / pharmacology
  • Superoxides / metabolism
  • Tumor Necrosis Factor-alpha / physiology*

Substances

  • Interleukin-1beta
  • Isoenzymes
  • Nitric Oxide Donors
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • Nitric Oxide
  • S-Nitrosoglutathione
  • Interferon-gamma
  • Arylamine N-Acetyltransferase
  • N-acetyltransferase 1
  • Glutathione