Paclitaxel inhibits N-acetyltransferase activity and gene expression in human stomach tumor cells (SC-M1)

Res Commun Mol Pathol Pharmacol. 2004:115-116:21-38.

Abstract

Evidence has shown that N-acetyltransferase (NAT) acetylated 2-aminofluorene (AF) to form N-acetyl-2-aminofluorene (AAF). Then it was metabolized by cytochrome P450 (CYP) enzyme to form ring or N-hydroxylated metabolites. Sulfotransferase and other enzymes participated to form the ultimate metabolites which bind to DNA to form DNA-AF adducts which may have led to cancer development. The aim of the present study is to demonstrate whether paclitaxel (taxol) can inhibit the NAT activity, NAT gene expression and DNA-AF adduct formation in human stomach tumor cell line (SC-M1). The activity of NAT was determined by high performance liquid chromatography (HPLC) assaying for the amounts of acetylated AF (AAF) or p-aminobenzoic acid (N-Ac-PABA) and nonacetylated AF or PABA. While SC-M1 cell cytosols were used for examining NAT activity, intacts cells were used for examining all three: NAT activity, gene expression and DNA-AF adduct formation. As compared with the control group, the paclitaxel- treated group showed decreased NAT activity and DNA-AF adduct formation in SC-M1 cells and the decrease was dose-dependent. The results also indicated that paclitaxel decreased the apparent values of K(m) and V(max) from SC-M1 cells in both cytosol and intact cells. Palitaxel did significantly affect NAT gene expression (NAT1 mRNA) in SC-M1 cells.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Acetylaminofluorene / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Arylamine N-Acetyltransferase / analysis
  • Arylamine N-Acetyltransferase / antagonists & inhibitors*
  • Arylamine N-Acetyltransferase / genetics
  • Carcinogens / metabolism
  • Cell Line, Tumor
  • Chromatography, High Pressure Liquid
  • Cytochrome P-450 Enzyme System / metabolism
  • DNA Adducts / antagonists & inhibitors
  • DNA Adducts / biosynthesis
  • Dose-Response Relationship, Drug
  • Gene Expression / drug effects*
  • Humans
  • Kinetics
  • Paclitaxel / pharmacology*
  • RNA, Messenger / metabolism
  • Stomach Neoplasms / enzymology*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology

Substances

  • Antineoplastic Agents, Phytogenic
  • Carcinogens
  • DNA Adducts
  • RNA, Messenger
  • Cytochrome P-450 Enzyme System
  • 2-Acetylaminofluorene
  • Arylamine N-Acetyltransferase
  • Paclitaxel