Biochemical changes and morphological alterations of liver and kidney in hamsters after administration of the HMG-coenzyme A reductase inhibitor, simvastatin: prevention and reversibility by mevalonate.
The present study analyses the effects of simvastatin, a specific inhibitor of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA reductase) in male Syrian hamsters fed a standard diet or a diet supplemented with 0.12% cholesterol and 20% coconut oil. In hamsters fed the standard diet, gastric administration of simvastatin (10 mg/kg/day) during 12 days was found to be lethal and to have hepatotoxic and nephrotoxic effects. This toxicity was exacerbated in hamsters fed a hyperlipidaemic diet and was preceded by a progressive anorexia and loss of body weight. Marked elevations in serum aspartate and alanine aminotransferase activities were associated with the organ lesions. All elevated biochemical changes and morphological alterations were prevented or reversed by coadministration of mevalonate, the product of the HMG-CoA reductase. It is suggested that the dramatic effect of simvastatin could result from depletion of a non-sterol metabolite of mevalonate in spite of a lack of protective effects of farnesol and geranylgeraniol in the following study. The toxicity of simvastatin could indeed result from the low basal activity of HMG-CoA reductase in hamster liver coupled with a prolonged inhibition of mevalonate synthesis.
Oms
P
P
Pierre Fabre Research Center, Castres, France.
Assie
N
N
Bruniquel
F
F
Degryse
A D
AD
van Haverbeke
G
G
Delhon
A
A
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D006224:Cricetinae; D004041:Dietary Fats / Q000008:administration & dosage; D004435:Eating / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008148:Lovastatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000633:toxicity; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology*; D009336:Necrosis; D019821:Simvastatin
D004041:Dietary Fats; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D019821:Simvastatin; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008798:Mevalonic Acid