Protective effect of creatine against RNA damage.
It is well documented that damage to DNA could be very harmful for all cells and is the source of several consequences such as cancer development, apoptosis or genetic diseases. In contrast, RNA damage is a poorly examined field in biomedical research, despite its potential to affect cell physiology. For example, a significant loss of RNA integrity has been demonstrated in advanced human atherosclerotic plaques as compared with non-atherosclerotic mammary arteries, and oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease. In the present study, we investigated whether RNA damage could be related to the exposure of particular xenobiotics and then we studied the potential protective activity of creatine against RNA-damaging activity of a series of chemicals with different mechanisms of action [ethyl methanesulfonate (EMS), H(2)O(2), doxorubicin, spermine NONOate, S-nitroso-N-acetylpenicillamine (SNAP)]. Since the protective effect against RNA damage can be mediated by different mechanisms, such as alterations of the rates of toxic agent absorption and uptake, trapping of electrophiles as well as free radicals, and protection of nucleophilic sites in RNA, we used two different treatment protocols (pre- and co-treatment) for understanding the mechanism of the inhibitory activity of creatine. We demonstrated that total RNA is susceptible to chemical attack by doxorubicin, H(2)O(2), spermine and SNAP. Creatine significantly reduced the RNA-damaging activity of only two of the toxic tested agents (H(2)O(2) and doxorubicin), while it lacked activity in counterstaining the RNA damage induced by the NO donors spermine and SNAP. Its inhibitory activity could be at least partially dependent on its capacity to directly scavenge free radicals and/or to maintain phosphocreatine store and ATP regeneration.
Fimognari
Carmela
C
Dipartimento di Farmacologia, Alma Mater Studiorum Università di Bologna, Bologna, Italy. carmela.fimognari@unibo.it
Sestili
Piero
P
Lenzi
Monia
M
Cantelli-Forti
Giorgio
G
Hrelia
Patrizia
P
D002478:Cells, Cultured; D003401:Creatine / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity; D004336:Drug Antagonism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008214:Lymphocytes / Q000187:drug effects*; D009153:Mutagens / Q000633:toxicity; D012313:RNA / Q000187:drug effects*
D009153:Mutagens; D012313:RNA; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D003401:Creatine