Mammalian cells become more susceptible to radiation-induced death and mutagenesis when restricted in their production of the natural polyamines putrescine, spermidine and spermine. The effects of polyamine deprivation are reversed by N-(2-mercaptoethyl)-1,3-diaminopropane (WR1065), a simple aminothiol that has been extensively studied for its radioprotectant properties. Because this compound and its oxidized derivative WR33278 bear some resemblance to the polyamines, it was hypothesized that radioprotection by WR1065 or its metabolites is derived, at least in part, from their ability to supplement the natural polyamines. To evaluate the ability of these aminothiol compounds to emulate polyamine function in intact cells, rat liver hepatoma (HTC) cells were treated with radioprotective doses of WR1065; the ability of this compound to affect various aspects of normal polyamine metabolism was monitored. Although cellular WR1065 was maintained at levels exceeding those of the polyamines, this aminothiol did not have any polyamine-like effect on the initial polyamine biosynthetic enzyme, ornithine decarboxylase, or on polyamine degradative reactions. On the contrary, treatment with relatively low levels of WR1065 resulted in an unexpected increase in putrescine and spermidine synthesis. WR1065 treatment enhanced the stability, and consequently the activity, of ornithine decarboxylase. This stabilization seems to result from a WR1065-induced delay in the synthesis of antizyme, a critical regulatory protein required in the feedback modulation of polyamine synthesis and transport. The increase in cellular spermidine induced by WR1065 might explain its antimutagenic properties, but is probably not a factor in protection against cell killing by radiation. This is the first evidence that compounds can be designed to control polyamine levels by targeting the activity of the regulatory protein antizyme.
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October 1998
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Research Article|
October 15 1998
Mammalian cell polyamine homeostasis is altered by the radioprotector WR1065
John L. A. MITCHELL;
John L. A. MITCHELL
1
1Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, U.S.A.
1To whom correspondence should be addressed (e-mail jmitchell@niu.edu).
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Jennifer RUPERT;
Jennifer RUPERT
1Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, U.S.A.
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Aviva LEYSER;
Aviva LEYSER
1Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, U.S.A.
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Gary G. JUDD
Gary G. JUDD
1Department of Biological Sciences, Northern Illinois University, DeKalb, IL 60115, U.S.A.
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Publisher: Portland Press Ltd
Received:
May 22 1998
Revision Received:
July 14 1998
Accepted:
August 15 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 335 (2): 329–334.
Article history
Received:
May 22 1998
Revision Received:
July 14 1998
Accepted:
August 15 1998
Citation
John L. A. MITCHELL, Jennifer RUPERT, Aviva LEYSER, Gary G. JUDD; Mammalian cell polyamine homeostasis is altered by the radioprotector WR1065. Biochem J 15 October 1998; 335 (2): 329–334. doi: https://doi.org/10.1042/bj3350329
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