The effect of paclitaxel on gene expression and activity of arylamine N-acetyltransferase and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cells.
N-Acetylation is recognized as the first step in arylamine metabolism. The enzyme responsible for N-acetylation is called arylamine N-acetyltransferase (NAT),which uses acetyl coenzyme A as the acetyl group donor. Paclitaxel has been shown to exhibit antineoplastic and anticancer activity. In this study, paclitaxel was selected to determine the inhibition of arylamine N-acetyltransferase activity, gene expression (NAT mRNA) and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cell line. Paclitaxel (0.01-l microM) did decrease the level of NAT mRNA in a dose-dependent manner. The results demonstrated that paclitaxel inhibited NAT activity and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cells in a dose-dependent manner. Using standard steady-state kinetic analysis, it was demonstrated that paclitaxel was a possible uncompetitive inhibitor to NAT activity in cytosols based on the decrease in apparent values of K(m) and V(max). This report is the first demonstration that paclitaxel affected human leukemia HL-60 cells NAT activity and DNA-2-aminofluorene adduct formation.
Lu
K H
KH
Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Chien-Kuo N. Road, Taichung 402, Taiwan, ROC.
Lin
K L
KL
Yang
C C
CC
Hsia
T C
TC
Hsiao
Y M
YM
Chou
M C
MC
Ho
H C
HC
Chung
J G
JG
D000107:Acetylation; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000737:chemistry*; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D018736:DNA Adducts / Q000187:drug effects*; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D005449:Fluorenes / Q000737:chemistry*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D007938:Leukemia / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D017239:Paclitaxel / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000972:Antineoplastic Agents, Phytogenic; D002273:Carcinogens; D018736:DNA Adducts; D005449:Fluorenes; C012177:2-aminofluorene; D001191:Arylamine N-Acetyltransferase; D017239:Paclitaxel