Differential effects of heterocyclic amines on poly(ADP-ribose) polymerase-1 and mono-ADP-ribosyltransferase A

Heterocyclic amines (HCAs) have been shown to be carcinogenic in a variety of experimental systems. The purpose of the present study was to determine the in vitro effect of HCAs on the activity of the DNA repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1). HCAs were also tested on the arginine-specific mono-ADP-ribosyltransferase A (MART-A), an enzyme involved in signal transduction and cytoskeletal realignment. 3-Amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) at 1 mM caused a 134% increase in PARP-1 activity and a 93% decrease in activity at 5 mM (IC(50) = 2.2 mM). This dual effect is unique among inhibitors of this enzyme. On the other hand, Trp-P-2 activated MART-A at all concentrations tested, the peak being at 3 mM (>171% increase). In contrast, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) inhibited concentration-dependently both enzymes, PARP-1 (IC(50) = 0.22 mM) and MART-A (IC(50) = 2.8 mM). With nine other HCAs tested, predominantly inhibitory effects were observed. These results may assist our understanding of the carcinogenic mechanism of action and the dose-dependency of HCAs in animal bioassays.