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Carcinogenesis Advance Access published online on February 19, 2004
Carcinogenesis, doi:10.1093/carcin/bgh112
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CANCER BIOLOGY

3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) triggers apoptosis by DNA double-strand breaks caused by inhibition of topoisomerase I

Bunsyo Shiotani 1 and Hitoshi Ashida 2*

1 Division of Life Science, Graduate School of Science and Technology, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
2 Department of Biofunctional Chemistry, Faculty of Agriculture, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan

* Corresponding author. E-mail: ashida{at}kobe-u.ac.jp.

Received 9 November 2003 ; revised 28 January 2004 ; accepted 4 February 2004

Abstract

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is one of the dietary carcinogens. At the initial step in the carcinogenic process, its exocyclic amino group is metabolically activated to the hydroxyamino derivative by the cytochrome P450 (CYP) 1A and 1B subfamily and then form DNA adducts, which are considered to be the main cause of DNA damage during the carcinogenic process. On the other hand, our previous study has shown that Trp-P-1 exhibits cytotoxicity to primary cultured rat hepatocytes, via induction of caspase-9-dependent apoptosis without being metabolized by CYP 1A1. In the present study, we investigated what type of DNA damage would be involved in the induction of apoptosis induced by Trp-P-1. When RL-34 cells derived from normal rat liver were treated with a high (30 µM) concentration of Trp-P-1, apoptotic events such as the loss of cell viability, nuclear condensation and the activation of caspase-3 were observed. In these apoptotic cells, intracellular topoisomerase I activity was inhibited and histone H2AX phosphorylation, which occurs after introduction of DNA double-strand breaks, was observed in the early phase of the apoptosis. On the other hand, treatment with a non-apoptotic concentration (1 µM) of Trp-P-1 increased the formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG). The formation of DNA adducts was detected at the almost same level in both cells exposed to the apoptotic and non-apoptotic concentrations of Trp-P-1. These results indicate that Trp-P-1-induced apoptosis was triggered by DNA double-strand breaks through the inhibition of topoisomerase I but not the formation of DNA adducts.


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