Tamoxifen inhibits arylamine N-acetyltransferase activity and DNA-2-aminofluorene adduct in human leukemia HL-60 cells.
Genetic regulation of acetyl coenzyme A-dependent N-acetyltransferase (NAT)and O-acetyltransferase (OAT) activities may play an important role in the metabolic activation of arylamine chemicals and carcinogens. N-acetylation is thought to be the first step in arylamine metabolism. The enzyme responsible for N-acetylation is called NAT. In this study, synthetic non-steroidal antiestrogen tamoxifen was selected for determining the inhibition of arylamine NAT activity, gene expression (NAT mRNA) and DNA-2-aminofluorene adduct formation in human leukemia HL-60 cell line. The results demonstrated that tamoxifen did not affect the level of NAT mRNA in HL-60 cells. But the results also showed that NAT activity and 2-Aminofluorene-DNA adduct formation in HL-60 cells were inhibited and decreased by tamoxifen in a dose-dependent manner when the doses of tamoxifen up to 100 micro M. We also examined the standard steady-state kinetic analysis, and the data showed that tamoxifen may be an uncompetitive inhibitor to NAT activity in cytosols based on the decrease apparent values of Km and Vmax. This report is the first finding that tamoxifen inhibited human leukemia HL-60 cells NAT activity and DNA-2-aminofluorene on adduct formation.
Lu
K H
KH
Institute of Medicine, Chung Shan Medical & Dental College, Taichung, Taiwan, ROC.
Lin
K L
KL
Hsia
T C
TC
Hung
C F
CF
Chou
M C
MC
Hsiao
Y M
YM
Chung
J G
JG
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D001191:Arylamine N-Acetyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002273:Carcinogens; D018736:DNA Adducts / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D013629:Tamoxifen / Q000633:toxicity*
D002273:Carcinogens; D018736:DNA Adducts; D013629:Tamoxifen; D015073:2-Acetylaminofluorene; D001191:Arylamine N-Acetyltransferase