3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) induces apoptosis inrat splenocytes and thymocytes by different mechanisms

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a potent carcinoge n present in cooked meat. Although the target of this carcinogen is mainly in the liver, Trp-P-1 is distributed in the thymus and spleen as well as in the Liver after administration. However, the cytotoxic effect of Trp-P-1 o n lymphocytes has not been examined in detail. In the present study, we inv estigated the cytotoxicity of Trp-P-1 against rat splenocytes and thymocyte s. Trp-P-1 reduced viability of both types of cells in the same manner, the LD50 at 6 h in culture was 15 muM, and the time for the 50% decrease in ce ll viability (t(1/2)) at 20 muM was 3 h. In both types of cells, Trp-P-1 ca used the activation of caspase-3-like proteases and the cleavage of poly(AD P-ribose) polymerase, both of which are biochemical markers of apoptosis. O n the other hand, DNA fragmentation occured in splenocytes, but not in thym ocytes although Trp-P-1 activated 32-34 kDa nucleases that may not be able to degrade DNA into nucleosomal units. These results indicated that Trp-P-1 induces apoptosis in both splenocytes and thymocytes by different mechanis ms in which distinct apoptotic pathways may exist downstream of the caspase cascade. (C) 2000 Elsevier Science B.V. All rights reserved.