The effects on lipid metabolism of 4-phenyl-5,5-dicarbethoxy-2-pyrrolidenone in Sprague Dawley rats.
4-Phenyl-5,5-dicarbethoxy-2-pyrrolidenone [XIV] treatment in Sprague Dawley rats caused significant reduction of serum cholesterol and triglyceride levels with reduction of VLDL and LDL cholesterol levels. The compound significantly reduced regulatory enzyme activities, e.g. ATP dependent citrate lyase, HMG CoA reductase, acyl CoA cholesterol acyl transferase, cholesterol-7-alpha-hydroxylase, sn-glycerol-3-phosphate acyl transferase and phosphatidylate phosphohydrolase. In tissue cultured cells, the compound suppressed LDL receptor activity and degradation, and elevated HDL receptor activity and HDL degradation. Rat bile cholesterol and phospholipids were elevated; however, overall bile acids were reduced. In situ loop studies suggest that the agent interfered with interhepatic reabsorption of cholesterol and cholic acids. At the therapeutic dose of compound XIV, no deleterious effects were demonstrated in mice.
Hall
I H
IH
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill 27559.
Wong
O T
OT
Reynolds
D J
DJ
Chang
J J
JJ
D000818:Animals; D002352:Carrier Proteins; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL; D008297:Male; D011760:Pyrrolidinones / Q000494:pharmacology* / Q000633:toxicity; D016601:RNA-Binding Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000187:drug effects; D011973:Receptors, LDL / Q000187:drug effects; D018110:Receptors, Lipoprotein
D002352:Carrier Proteins; D008075:Lipoproteins, HDL; D011760:Pyrrolidinones; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; C031616:high density lipoprotein receptors; C041986:4-phenyl-5,5-dicarbethoxy-2-pyrrolidinone; C075197:high density lipoprotein binding protein