Paclitaxel (taxol) inhibits the arylamine N-acetyltransferase activity and gene expression (mRNA NAT1) and 2-aminofluorene-DNA adduct formation in human bladder carcinoma cells (T24 and TSGH 8301).
Acetylator polymorphism in man results from differential expression of human liver N-acetyltransferase. N-Acetyltransferase enzyme activity has been demonstrated to be involved in some types of chemical carcinogenesis. Paclitaxel (taxol) had been shown to affect N-acetyltransferase activity of human lung cancer cells. In this study, paclitaxel was chosen to investigate the effects of arylamine N-acetyltransferase activity (N-acetylation of substrate), gene expression and 2-aminofluorene-DNA adduct formation in human bladder carcinoma cell lines (T24 and TSGH 8301). The N-acetyltransferase activity (N-acetylation of substrates) was determined by high performance liquid chromatography assaying for the amounts of acetylated 2-aminofluorene and p-aminobenzoic acid and nonacetylated 2-aminofluorene and p-aminobenzoic acid. Intact human bladder carcinoma T24 and TSGH 8301 cells were used for examining N-acetyltransferase activity, gene expression and 2-aminofluorene-DNA adduct formation. The results demonstrated that the N-acetyltransferase activity, gene expression (NAT1 mRNA) and 2-aminofluorene-DNA adduct formation in intact human bladder carcinoma cells were inhibited and decreased by paclitaxel in a dose-dependent manner. The effects of paclitaxel on the apparent values of Km and Vmax of N-acetyltransferase enzyme from intact human bladder carcinoma cells were also determined in these cell lines. A marked influence of paclitaxel was observed on the decreasing apparent values of Km and Vmax from intact human bladder carcinoma cells (T24 and TSGH 8301). Thus, paclitaxel is an uncompetitive inhibitor to the NAT enzyme.
Yang
Ching-Chiang
CC
Department of Urology, China Medical College Hospital, No. 2, Yuh-Der Road,Taichung 404, Taiwan, Republic of China.
Chen
Guang-Wei
GW
Lu
Hsueh-Fu
HF
Wang
Der-Yuan
DY
Chen
Yi-Shuan
YS
Chung
Jing-Gung
JG
D010129:4-Aminobenzoic Acid / Q000378:metabolism; D000107:Acetylation; D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005449:Fluorenes / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes; D008297:Male; D017239:Paclitaxel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000201:enzymology*
C052668:2-aminofluorene-DNA complex; D000970:Antineoplastic Agents; D018736:DNA Adducts; D005449:Fluorenes; D007527:Isoenzymes; D012333:RNA, Messenger; D000123:Acetyltransferases; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; D017239:Paclitaxel; D010129:4-Aminobenzoic Acid