Upregulation of calpastatin in regenerating and developing rat liver: role in resistance against hepatotoxicity.
Acute liver failure induced by hepatotoxic drugs results from rapid progression of injury. Substantial research has shown that timely liver regeneration can prevent progression of injury leading to a favorable prognosis. However, the mechanism by which compensatory regeneration prevents progression of injury is not known. We have recently reported that calpain released from necrotic hepatocytes mediates progression of liver injury even after the hepatotoxic drug is cleared from the body. By examining expression of calpastatin (CAST), an endogenous inhibitor of calpain in three liver cell division models known to be resistant to hepatotoxicity, we tested the hypothesis that increased CAST in the dividing hepatocytes affords resistance against progression of injury. Liver regeneration that follows CCl(4)-induced liver injury, 70% partial hepatectomy, and postnatal liver development were used. In all three models, CAST was upregulated in the dividing/newly divided hepatocytes and declined to normal levels with the cessation of cell proliferation. To test whether CAST overexpression confers resistance against hepatotoxicity, CAST was overexpressed in the livers of normal SW mice using adenovirus before challenging them with acetaminophen (APAP) overdose. These mice exhibited markedly attenuated progression of liver injury and 57% survival. Whereas APAP-bioactivating enzymes and covalent binding of the APAP-derived reactive metabolites remained unaffected, degradation of calpain specific target substrates such as fodrin was significantly reduced in these mice. In conclusion, CAST overexpression could be used as a therapeutic strategy to prevent progression of liver injury where liver regeneration is severely hampered.
Limaye
Pallavi B
PB
Department of Toxicology, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209-0495, USA.
Bhave
Vishakha S
VS
Palkar
Prajakta S
PS
Apte
Udayan M
UM
Sawant
Sharmilee P
SP
Yu
Songtao
S
Latendresse
John R
JR
Reddy
Janardan K
JK
Mehendale
Harihara M
HM
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors; D002251:Carbon Tetrachloride / Q000633:toxicity; D002455:Cell Division; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000254:growth & development / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; D012333:RNA, Messenger; D000082:Acetaminophen; C033668:calpastatin; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D002154:Calpain