Continuous oxidative stress due to activation of polyamine catabolism accelerates aging and protects against hepatotoxic insults.
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 N (1)-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 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 age-related repression of the different antioxidant enzymes served as a protection against the hepatotoxic effects of carbon tetrachloride and thioacetamide.
Cerrada-Gimenez
Marc
M
Biotechnology and Molecular Medicine, A.I. Virtanen Institute, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, P.O. Box 1627, 70211, Kuopio, Finland. Marc.CerradaGimenez@uef.fi
Pietilä
Marko
M
Loimas
Suvikki
S
Pirinen
Eija
E
Hyvönen
Mervi T
MT
Keinänen
Tuomo A
TA
Jänne
Juhani
J
Alhonen
Leena
L
D000123:Acetyltransferases / Q000235:genetics*; D000375:Aging / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology*; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D011700:Putrescine / Q000378:metabolism / Q000494:pharmacology; D013095:Spermidine / Q000378:metabolism / Q000494:pharmacology; D013096:Spermine / Q000378:metabolism / Q000494:pharmacology; D013853:Thioacetamide / Q000494:pharmacology; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D002251:Carbon Tetrachloride; D011073:Polyamines; D011700:Putrescine; D013095:Spermidine; D013096:Spermine; D013853:Thioacetamide; D016159:Tumor Suppressor Protein p53; D000099228:Diamine N-Acetyltransferase