alpha-Methylspermidine protects against carbon tetrachloride-induced hepatic and pancreatic damage.
The role of polyamines in carbon tetrachloride (CCl(4))-induced organ injury was studied in syngenic rats and transgenic rats with activated polyamine catabolism. In syngenic rats, administration of CCl(4) resulted in the induction of hepatic spermidine/spermine N(1)-acetyltransferase (SSAT), accumulation of putrescine, reduction in spermine level and appearance of moderate hepatic injury within 24 h. Upon treatment with CCl(4), transgenic rats overexpressing SSAT displayed induction of both hepatic and pancreatic SSAT, with subsequent accumulation of putrescine and decrease of both spermidine and spermine pools. Administration of CCl(4) in SSAT transgenic rats induced not only massive hepatic injury, but also severe acute necrotizing pancreatitis. Pretreatment of the animals with catabolically stable functional polyamine mimetic, alpha-methylspermidine (MeSpd) prevented pancreatic and hepatic injury in SSAT rats and markedly reduced liver damage in syngenic animals. As assessed by immunostaining of proliferating cell nuclear antigen, MeSpd increased the amount of regenerating hepatocytes in both genotypes. These results show that CCl(4) induces hepatic and pancreatic polyamine catabolism, and the extent of organ damage correlates with the degree of polyamine depletion. Furthermore, MeSpd protects against CCl(4)-induced hepatic and pancreatic damage and promotes tissue regeneration.
Hyvönen
Mervi T
MT
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Kuopio, PL 1627, 70211 Kuopio, Finland. mervi.hyvonen@uku.fi
Sinervirta
Riitta
R
Grigorenko
Nikolay
N
Khomutov
Alex R
AR
Vepsäläinen
Jouko
J
Keinänen
Tuomo A
TA
Alhonen
Leena
L
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011073:Polyamines / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage*; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013095:Spermidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D002251:Carbon Tetrachloride; D011073:Polyamines; D020011:Protective Agents; D013095:Spermidine; D000099228:Diamine N-Acetyltransferase; C073193:1-methylspermidine