T. Hashimoto et al., 3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) induces apoptosis inrat splenocytes and thymocytes by different mechanisms, MUT RES-F M, 457(1-2), 2000, pp. 57-67
Citations number
49
Categorie Soggetti
Molecular Biology & Genetics
Journal title
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS
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.