Lovastatin decreases mortality and improves liver functions in fulminant hepatic failure from 90% partial hepatectomy in rats.
OBJECTIVE
Liver insufficiency occurs when the liver cannot perform critical functions such as ammonia metabolism, gluconeogenesis, or production of coagulation factors The hypothesis of this study was that decreased function of existing hepatocytes may contribute to hepatic failure, and that the function of these cells might be increased pharmacologically. Lovastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that inhibits cholesterol biosynthesis and affects the activity of some signal transduction pathways and liver transcription factors. Changes in hepatic transcription factors during liver regeneration might result in decreased liver functions, and lovastatin might prevent these changes


METHODS
Rats received 90% partial hepatectomy (90% PH), and either lovastatin or vehicle alone daily. Survival and liver functions were assessed.


RESULTS
Lovastatin increased survival to 58% (vs. 6% in controls that received 90% PH without drug), decreased the peak ammonia level to 427 microM (vs. 846 microM in controls), increased the nadir of glucose to 88 mg/dl (vs. 57 mg/dl in controls), decreased the peak prothrombin time to 23 s (vs 29 s in controls), and decreased the peak activated partial thromboplastin time to 29 s (vs. 39 s in controls). The full survival and metabolic benefits were observed when lovastatin was started at 30 min after 90% PH, but lovastatin was less efficacious when started at later times.


CONCLUSIONS
Lovastatin increases the function of existing hepatocytes and might be used to improve liver function after extensive hepatic resection.
Cai
S R
SR
Department of Internal Medicine, Washington University School of Medicine, USA.
Motoyama
K
K
Shen
K J
KJ
Kennedy
S C
SC
Flye
M W
MW
Ponder
K P
KP
D000641:Ammonia / Q000097:blood; D000818:Animals; D001780:Blood Coagulation Tests; D001786:Blood Glucose / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D006498:Hepatectomy; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D017093:Liver Failure / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D008111:Liver Function Tests; D008115:Liver Regeneration / Q000187:drug effects* / Q000502:physiology; D008148:Lovastatin / Q000494:pharmacology*; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015996:Survival Rate
D001786:Blood Glucose; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000641:Ammonia; D008148:Lovastatin