Paclitaxel inhibits N-acetyltransferase activity and gene expression in human stomach tumor cells (SC-M1).
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.
Hsia
Te-Chun
TC
Department of Internal Medicine, China Medical University Hospital, No 2, Yuh-Der Road, Taichung 404, Taiwan, ROC.
Yang
Jen-Hung
JH
Lin
Hui-Ju
HJ
Yu
Chun-Shu
CS
Yu
Fu-Shun
FS
Chung
Jing-Gung
JG
D015073:2-Acetylaminofluorene / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D002273:Carcinogens / Q000378:metabolism; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D018736:DNA Adducts / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D018736:DNA Adducts; D012333:RNA, Messenger; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D001191:Arylamine N-Acetyltransferase; D017239:Paclitaxel