Biochemical changes and morphological alterations of the liver in guinea-pigs after administration of simvastatin (HMG CoA reductase-inhibitor).
Simvastatin is a potent competitive inhibitor of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) which is the rate-limiting enzyme of cholesterol synthesis. In guinea-pigs, administration of a high oral dose of simvastatin (125 mg/kg/day at the beginning of the study) during 18 days had a major hepatotoxic effect whereas a lower oral dose (30 mg/kg/day) did not seem to cause any liver damage. A significant reduction in microsomal Cyt P 450 content was only observed on a high dose of simvastatin whereas HMG CoA reductase activity was reduced in the group with the low simvastatin dose. The hepatic microsomal aminopyrine N-demethylase activity remained unchanged in all groups. The liver lesion was hepatocellular necrosis accompanied in some animals by a biliary duct proliferation. It was associated with a 10-fold elevation in serum aspartate and alanine aminotransferase activities, as well as a great reduction in daily food intake and body weight (28%). The hepatotoxicity of simvastatin could result from the low basal content of HMG-CoA reductase in guinea-pig liver, the prolonged inhibition of mevalonate synthesis and probably, from the absence of HMG-CoA reductase enzyme de novo synthesis.
Horsmans
Y
Y
Laboratory of Pharmacotherapeutics, Catholic University of Louvain, Bruxelles, Belgium.
Desager
J P
JP
Harvengt
C
C
D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D003084:Colestipol / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D006168:Guinea Pigs; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D009336:Necrosis; D019821:Simvastatin
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D008148:Lovastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D000633:Aminopyrine N-Demethylase; D003084:Colestipol