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Vol. 57, Issue 3, 468-473, March 2000
Department of Pharmacology, University of Western Australia,
Nedlands, Western Australia, 6907, Australia (N.J.B., K.F.I., R.F.M.);
Laboratory for Cancer Medicine, Royal Perth Hospital, Perth, Western
Australia, 6000, Australia (N.J.B., R.F.M.); and Clinical Pharmacology
and Toxicology Laboratory, The Western Australian Centre for Pathology
and Medical Research, Nedlands, Western Australia, 6009, Australia
(K.F.I.)
Arylamine N-acetyltransferase-1 (NAT1) is a
polymorphically expressed enzyme that is widely distributed throughout
the body. In the present study, we provide evidence for
substrate-dependent regulation of this enzyme. Human peripheral blood
mononuclear cells cultured in medium supplemented with
p-aminobenzoic acid (PABA; 6 µM) for 24 h showed
a significant decrease (50-80%) in NAT1 activity. The loss of
activity was concentration-dependent (EC50 ~ 2 µM)
and selective because PABA had no effect on the activity of
constitutively expressed lactate dehydrogenase or aspartate
aminotransferase. PABA also induced down-regulation of NAT1 activity in
several human cell lines grown at confluence. Substrate-dependent
down-regulation was not restricted to PABA. Addition of other NAT1
substrates, such as p-aminosalicylic acid, ethyl-p-aminobenzoate, or p-aminophenol
to peripheral blood mononuclear cells in culture also resulted in
significant (P < .05) decreases in NAT1 activity.
However, addition of the NAT2-selective substrates sulfamethazine,
dapsone, or procainamide did not alter NAT1 activity. Western blot
analysis using a NAT1-specific antibody showed that the loss of NAT1
activity was associated with a parallel reduction in the amount of NAT1
protein (r2 = 0.95). Arylamines that
did not decrease NAT1 activity did not alter NAT1 protein levels.
Semiquantitative reverse transcriptase polymerase chain reaction of
mRNA isolated from treated and untreated cells revealed no effect of
PABA on NAT1 mRNA levels. We conclude that NAT1 can be down-regulated
by arylamines that are themselves NAT1 substrates. Because NAT1 is
involved in the detoxification/activation of various drugs and
carcinogens, substrate-dependent regulation may have important
consequences with regard to drug toxicity and cancer risk.
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