Involvement of reactive oxygen species in the immunosuppressive effect of 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), a food-born carcinogenic heterocyclic amine

Abstract

A heterocyclic amine, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the potent food-borne dietary carcinogens derived mainly from burnt meat products. In the present study, we investigated the immunosuppressive effect of Trp-P-1 on the blastogenesis of lymphocytes prepared from spleen and thymus of Balb/c mice. Trp-P-1 inhibited, in a dose-dependent manner, proliferation of splenocytes in response to a B-cell mitogen, lipopolysaccharide and of both splenocytes and thymocytes in response to T-cell mitogens, concanavalin A and phytohemagglutinin, or non-receptor-mediated stimuli, phobol 12-myristate 13-acetate/ionomycin. Interestingly, Trp-P-1-inhibited proliferation in the splenocytes was restored almost completely by N-acetyl-l-cysteine (NAC) and partially by glutathione (GSH), whereas no effect was found when superoxide dismutase and catalase were used. Moreover, Trp-P-1 enhanced the mitogen-induced NF-kappaB binding activity to its cognate binding sequences, which is known to be mediated by intracellular reactive oxygen species (ROS) generation. Collectively, these results suggest that the immunosuppressive effect of Trp-P-1 is mediated by suppressing blastogenesis of lymphocytes via intracellular generation of ROS sensitive to NAC and/or GSH.