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© 1990 Oxford University Press

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Mutational specificity of the carcinogen 3-amino-1-methyl-5H-pyrido[4,3-b]-indole in mammalian cells

Toshiaki Akagi 1 2, Katsuyasu Morota 3, Hiroaki Iyehara-Ogawa 3, Hiroshi Kimura 4 and Takesi Kato 1 5

1Department of Fundamental Radiology, Osaka University, Medical School Osaka 530
3Faculty of Engineering, Kyushu Institute of Technology Kitakyushu 804
4Department of Experimental Radiology, Shiga University of Medical Science Shiga 520–21, Japan

2Present address: Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663, Japan

5To whom correspondence should be addressed

We have used the pZipHprtNeo shuttle vector to determine the types of DNA sequence alterations induced by a potent carcinogen 3-amino-l-methyl-5H-pyrido[4,3-b]indole (Trp-P2). The shuttle vector contains a human cDNA hprt as the target gene and is stably integrated into a chromosome of the mouse cell line VH12. After Trp-P2 treatment, 59 independent HPRT– mutant clones of VH12 were isolated and altered sequences of the mutant hprt– cDNA genes were determined. Mutations induced by Trp-P2 comprised a variety of events; base substitutions, frameshifts, deletions and complex. Frameshifts were the most frequent mutational events (51%), and base substitutions were the next most frequent (30%) followed by deletions (14%). Examination of the DNA sequence context in the mutant genes revealed that ~70% of mutations induced by Trp-P2 occurred at G:C sites and thymine residues were the suggested target for the remainder of mutations. The results seem consistent with the previously reported finding that in vivo, metabolically activated Trp-P2 specifically binds to the C8 position of guanine residues in DNA to form C8G–Trp-P2 adducts (Hashimoto et al., Mutat. Res., 105, 9–13, 1982). As for molecular mechanisms, we showed that slippage and slippage misalignment could predict the generation of a large portion of Trp-P2-induced mutations found in the cDNA gene.


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