Gossypol activates pancreatic polyamine catabolism in normal rats and induces acute pancreatitis in transgenic rats over-expressing spermidine/spermine N1-acetyltransferase.
BACKGROUND
The male antifertility agent gossypol has been reported to induce spermidine/spermine N1-acetyltransferase (SSAT) in canine prostate cells. As SSAT is the rate-controlling enzyme in the catabolism of the polyamines and is involved in the development of acute pancreatitis in a recent transgenic rat model, we exposed normal and transgenic rats over-expressing SSAT to gossypol to evaluate its effect on pancreatic polyamine metabolism and organ integrity.


METHODS
Pancreatic SSAT activity, polyamine pools, pancreatic histology and plasma 2-amylase activity were determined after different doses of gossypol.


RESULTS
Gossypol increased pancreatic putrescine and decreased spermidine and spermine pools in normal rats accompanied by tissue oedema and significantly elevated plasma amylase activity. In transgenic rats, the drug strikingly induced SSAT, profoundly depleted the higher polyamines and caused distinct pancreatitis. The combination of gossypol at doses harmless to transgenic pancreas with an inhibitor of polyamine oxidase caused massive synergistic induction of SSAT, profound depletion of the polyamine pools and acute pancreatitis.


CONCLUSIONS
The results indicate that gossypol induces pancreatitis through an activation of polyamine catabolism.
Räsänen
T L
TL
Dept. of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland.
Alhonen
L
L
Sinervirta
R
R
Uimari
A
A
Kaasinen
K
K
Keinänen
T
T
Herzig
K H
KH
Jänne
J
J
D000123:Acetyltransferases / Q000187:drug effects / Q000378:metabolism*; D000208:Acute Disease; D000818:Animals; D030801:Animals, Genetically Modified; D003272:Contraceptive Agents, Male / Q000494:pharmacology*; D004195:Disease Models, Animal; D006072:Gossypol / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects* / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced* / Q000201:enzymology*; D011073:Polyamines / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D003272:Contraceptive Agents, Male; D006072:Gossypol; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase