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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg054
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received November 22, 2002; accepted January 31, 2003
© 2003 Society of Toxicology

In Vitro Toxicology and Alternative Testing

Synergistic Role of 3-Hydroxy-3 Methylglutaryl Coenzyme A Reductase and Cholesterol 7{alpha}-Hydroxylase in the Pathogenesis of Manganese-Bilirubin Induced Cholestasis in Rats

Marie-Yvonne Akoume 1, Shahid Perwaiz 1, Ibrahim M. Yousef 1*, Gabriel L. Plaa 2

1 Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada H3C 3J7; Centre de recherche de l'hopital Sainte Justine, Montreal, Quebec, Canada H3T 1C5
2 Département de Pharmacologie, Université de Montréal, Montréal, Québec, Canada H3C 3J7

* To whom correspondence should be addressed. E-mail: ibrahim.yousef{at}umontreal.ca.


  Abstract

Manganese (Mn) and bilirubin (BR) induce intrahepatic cholestasis when injected sequentially. It was suggested that accumulation of newly synthesised cholesterol in the canalicular membrane is an initial step in the development of cholestasis. To clarify the involvement of cholesterol in the pathogenesis of Mn-BR-induced cholestasis, we examined biliary secretion and liver subcellular distribution of lipids in the cholestatic conditions (Mn-BR combination). We also examined hepatic metabolism of cholesterol under cholestatic and non-cholestatic (Mn or BR given alone) conditions. The Mn-BR combination reduced bile flow by 50%, and bile acid, phospholipids and cholesterol output by 42, 75 and 90%, respectively. There was a dramatic impairment of cholate excretion but not chenodeoxycholate excretion. Phosphatidylcholine species secreted into bile were unchanged, and microsomal total phospholipid content was significantly increased. Although, there was no changes in liver membrane phospholipid content; the cholesterol/phospholipid ratio was increased by more than 50% in the canalicular fraction. Despite the increased concentration of cholesterol in canalicular membrane the activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, key enzyme in cholesterol synthesis, and cholesterol 7{alpha}-hydroxylase, key enzyme in cholesterol conversion to bile acids, were significantly reduced. However, the injection of Mn alone increased significantly both enzymes, while BR alone inhibited cholesterol 7{alpha}-hydroxylase by 62%, without affecting HMG-CoA reductase. In conclusion, the critical cholestatic events in Mn-Br-induced cholestasis appear to be mediated through the synergistic effects of Mn and BR acting on synthesis and degradation of cholesterol.

Cholesterol, Phospholipid, Cholate, Canalicular Membranes, HMG-CoA reductase, Cholesterol 7{alpha}-hydroxylase .


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