Retrorsine: a kinetic study of its influence on rat liver regeneration in the portal branch ligation model.
BACKGROUND
Retrorsine, a naturally occurring pyrrolizidine alkaloid, impairs liver regeneration after partial hepatectomy by mechanisms that are still unclear.


OBJECTIVE
The aim of the study was to clarify the influence of retrorsine on cell cycle progression in the regenerating liver lobes of rats after portal branch ligation (PBL).


METHODS
Liver weight, protein and DNA contents, DNA synthesis (5'-bromodeoxyuridine (BrdU) incorporation) and cellular levels of Cyclin E, CDK-2, CDK-4 and proliferating cell nuclear antigen (PCNA) were assessed before and 24, 48, 72 and 168 h after PBL.


RESULTS
Before surgery, higher levels of cyclin E, CDK-2, CDK-4 and PCNA as well as BrdU incorporation were found in the liver of retrorsine-treated rats than in untreated rats. Liver weight gain, protein and DNA synthesis as well as induction of cell cycle related proteins were all strongly impaired by retrorsine in the regenerating lobes after PBL.


CONCLUSIONS
In conclusion, retrorsine impairs liver regeneration in the PBL model not only by an S or G2/M phase block, but also by a block located before the G1/S transition of the cell cycle.
Picard
Christian
C
Gastroenterology Laboratory, University of Louvain Medical School, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium.
Lambotte
Luc
L
Starkel
Peter
P
Sempoux
Christine
C
Saliez
Alain
A
Van Den Berge
Véronique
V
de Saeger
Christine
C
Horsmans
Yves
Y
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D042846:CDC2-CDC28 Kinases / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004195:Disease Models, Animal; D007700:Kinetics; D008026:Ligation; D008107:Liver Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D009929:Organ Size; D011169:Portal Vein; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015430:Weight Gain / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D019927:Cyclin E; D018809:Proliferating Cell Nuclear Antigen; D011518:Proto-Oncogene Proteins; D011763:Pyrrolizidine Alkaloids; D004247:DNA; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D001973:Bromodeoxyuridine; C003300:retrorsine