Xanthine oxidase-derived oxygen radicals play significant roles in the development of chronic pancreatitis in WBN/Kob rats.
BACKGROUND
Although oxygen-derived free radicals are known to play a role in cell injury and DNA alterations, the role of active oxidants in chronic pancreatitis has not been fully elucidated. Using WBN/Kob rats, which spontaneously develop chronic pancreatitis-like lesions, we investigated whether xanthine oxidase (XOD)-derived oxygen radicals are involved in pancreatic tissue injury.


METHODS
WBN/Kob rats were fed a control or a tungsten diet. The latter depletes XOD activity. Histologic al changes, glutathione (GSH) content and XOD and superoxide dismutase (SOD) activities were determined in pancreatic tissue. Pancreatic 8-hydroxy-deoxyguanosine (8-OH-dG) levels and lithostathine mRNA were also examined.


RESULTS
In WBN/Kob rats, parenchymal destruction and fibrosis developed at approximately 12 weeks of age and progressed with each month. The activity of XOD was significantly higher in the early period (8-12 weeks), whereas the levels of GSH and SOD decreased after 16 weeks. Levels of 8-OH-dG in WBN/Kob rats were significantly elevated at 16 weeks. Lithostathine mRNA levels started to increase at 8 weeks, but were suppressed at 16 weeks. The tungsten diet significantly attenuated the histological changes in WBN/Kob rats. The increase in pancreatic XOD activity and 8-OH-dG content in WBN/Kob rats was significantly inhibited by the tungsten diet and lithostathine mRNA levels remained high at 16 weeks.


CONCLUSIONS
These results suggest that oxygen radicals generated by XOD play an important role in oxidative DNA damage and the development of chronic pancreatic injury.
Zeki
Shigeyuki
S
Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
Miura
Soichiro
S
Suzuki
Hidekazu
H
Watanabe
Naoyuki
N
Adachi
Masayuki
M
Yokoyama
Hirokazu
H
Horie
Yoshinori
Y
Saito
Hidetsugu
H
Kato
Shinzo
S
Ishii
Hiromasa
H
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000681:Amylases / Q000097:blood; D000818:Animals; D001835:Body Weight; D002135:Calcium-Binding Proteins / Q000235:genetics; D002908:Chronic Disease; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D051847:Lithostathine; D009419:Nerve Tissue Proteins; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D011393:Procollagen-Proline Dioxygenase / Q000097:blood; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D014969:Xanthine Oxidase / Q000378:metabolism*
D002135:Calcium-Binding Proteins; D051847:Lithostathine; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C497616:Reg1a protein, rat; D000080242:8-Hydroxy-2'-Deoxyguanosine; D011393:Procollagen-Proline Dioxygenase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D000681:Amylases; D003849:Deoxyguanosine; D005978:Glutathione