Continuous oxidative stress due to activation of polyamine catabolism accelerates aging and protects against hepatotoxic
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ORIGINAL PAPER
Continuous oxidative stress due to activation of polyamine catabolism accelerates aging and protects against hepatotoxic insults Marc Cerrada-Gimenez • Marko Pietila¨ • Suvikki Loimas • Eija Pirinen • Mervi T. Hyvo¨nen • Tuomo A. Keina¨nen • Juhani Ja¨nne • Leena Alhonen
Received: 12 February 2010 / Accepted: 10 June 2010 / Published online: 25 June 2010 Ó Springer Science+Business Media B.V. 2010
Abstract Enhanced polyamine catabolism via polyamine acetylation-oxidation elevates the oxidative stress in an organism due to increased production of reactive oxygen species (ROS). We studied a transgenic mouse line overexpressing the rate limiting enzyme in the polyamine catabolism, spermidine/ spermine N1-acetyltransferase (SSAT) that is characterized by increased putrescine and decreased spermidine and spermine pools. In order to protect the mice from the chronic oxidative stress produced by the activation of polyamine catabolism, the hepatic expression of the transcription factor p53 was found threefold elevated in the transgenic mice. In addition, the prolonged activation of p53 accelerated the aging of transgenic mice and reduced their lifespan (50%). Aging was associated with decreased antioxidant enzyme activities. In the transgenic mice the activities
Electronic supplementary material The online version of this article (doi:10.1007/s11248-010-9422-5) contains supplementary material, which is available to authorized users. M. Cerrada-Gimenez (&) M. Pietila¨ S. Loimas E. Pirinen M. T. Hyvo¨nen T. A. Keina¨nen J. Ja¨nne L. Alhonen Biotechnology and Molecular Medicine, A.I. Virtanen Institute, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, P.O. Box 1627, 70211 Kuopio, Finland e-mail: [email protected]
of catalase and Cu, Zn-superoxide dismutase (SOD) were 42 and 23% reduced respectively, while the expression of CYP450 2E1 was 60% decreased and oxidative stress measured as protein carbonyl content was tenfold elevated. In the transgenic mice, the agerelated repression of the different antioxidant enzymes served as a protection against the hepatotoxic effects of carbon tetrachloride and thioacetamide. Keywords Polyamines Aging Oxidative stress p53 Carbon tetrachloride Thioacetamide Introduction Polyamines are a group of biological polycations found in all eukaryotic cells. They include the diamine putrescine, the triamine spermidine, and the tetramine spermine. Polyamine homeostasis and metabolism are tightly controlled during normal cellular conditions (Wallace 2003). The biosynthesis of polyamines is controlled by ornithine decarboxylase (ODC, EC: 4.1.1.17) and S-adenosyl-L-methionine decarboxylase (AdoMetDC. EC: 4.1.1.50). The rate-limiting enzyme of polyamine catabolism is spermidine/spermine N1-acetyltransferase (SSAT. EC: 2.3.1.57). Polyamines have a wide variety of functions: they are involved in the regulation of transcription and translation, and they interact with inward rectifying K? channels, N-methyl-D-aspartate receptors, and membrane-bo
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