Inactivation of human arylamine N-Acetyltransferase 1 by the hydroxylamine of p-Aminobenzoic acid
Section snippets
Chemicals
Ficoll-Paque and enhanced chemiluminescence detection reagent were purchased from Amersham International. Cell culture medium was purchased from GIBCO and fetal bovine serum was from WA Serum Laboratories. PABA, p-nitrobenzoic acid, DTT, DMSO, N,N-dimethylformamide, horseradish peroxidase-conjugated goat anti-rabbit immunoglobulin, and phorbol 12-myristate 13-acetate were obtained from Sigma Chemical Co. Diethyl ether, zinc dust, and ammonium chloride were purchased from BDH, and AcCoA was from
Effect of N-OH-PABA on NAT1 activity in cultured PBMC
Human PBMC were cultured in BME medium for 24 hr in the absence or presence of 50 μM N-OH-PABA. Cells treated with N-OH-PABA showed a time-dependent loss in NAT1 activity (measured as the N-acetylation of PABA in vitro), with maximal loss occurring within 4 hr (Fig. 1a). PBMC cultured for 24 hr in the absence of N-OH-PABA, but with an equivalent amount of vehicle (0.5% DMSO:ethanol, 4:1), showed no significant loss in NAT1 activity compared to freshly isolated cells (19.5 ± 0.5 and 17.6 ± 0.7
Discussion
It is now well documented that human NATs are polymorphically expressed, with 24 NAT1 and 26 NAT2 variant alleles currently identified. Since both isozymes are capable of bioactivating a number of potential human carcinogens, recent studies into NATs have been primarily focussed on identifying variant alleles and determining how they modulate risk for various types of cancers [reviewed in 52]. However, wide variation in NAT1 activity observed within a single phenotype [9] suggests that
Acknowledgements
This work was supported by a grant from the Medical Research Foundation, Royal Perth Hospital. N.J.B. was supported by the Elizabeth Stalker McEwan Trust. We are grateful to Prof. Edith Sim for the NAT1 antibody used in this study and to Dean Naisbitt for N-OH-SMX.
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