title: The thienotriazolodiazepine Ro 11-1464 increases plasma apoA-I and promotes reverse cholesterol transport in human apoA-I transgenic mice.
abstract: OBJECTIVE
  Ro 11-1464 is a thienotriazolodiazepine previously described to selectively stimulate apolipoprotein A-I (apoA-I) production and mRNA level in human liver cells. Here, we studied its effects upon oral administration to human apoA-I transgenic (hapoA-I) mice.
  
  
  METHODS
  HapoA-I mice were treated for 5 days with increasing doses of Ro 11-1464. Macrophage reverse cholesterol transport (mph-RCT) was assessed by following [(3) H]-cholesterol mobilization from pre-labelled i.p. injected J774 macrophages to plasma, liver and faeces. Effects on plasma lipids, apoproteins, lecithin-cholesterol : acyltransferase (LCAT) and liver enzymes, as well as on faecal excretion of cholesterol and bile salts, and on liver lipids and mRNA contents were determined.
  
  
  RESULTS
  Treatment with Ro 11-1464 300 mg·kg(-1) ·day(-1) resulted in a nearly 2-fold increase in plasma apoA-I, a 2- to 3-fold increase in the level of large sized-pre-β high-density lipoprotein and a 3-fold selective up-regulation of hepatic apoA-I mRNA, but a marked decrease in all plasma lipids and LCAT activity. Mpm-RCT was decreased in blood but markedly increased in faecal sterols (4-fold) and bile acids (1.7-fold). However, liver weight and liver enzymes in plasma were also increased, in parallel with an increase in liver cholesterol ester content (all these effect being significant).
  
  
  CONCLUSIONS
  In this model Ro 11-1464 causes increased hepatic expression and plasma levels of apoA-I and a suppression of LCAT, and a marked enhancement of reverse cholesterol transport, but also some symptoms of liver toxicity. The compound may therefore be a prototype for a next generation of anti-atherosclerotic medicines.
authors: Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Università degli Studi di Parma, Parma, Italy.
authors: I
authors: I
authors: Zanotti
authors: C
authors: C
authors: Maugeais
authors: M
authors: M
authors: Pedrelli
authors: M
authors: M
authors: Gomaraschi
authors: P
authors: P
authors: Salgam
authors: L
authors: L
authors: Calabresi
authors: F
authors: F
authors: Bernini
authors: H
authors: H
authors: Kempen
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism; D001381:Azepines / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: C570525:9-methyl-4-phenyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepine; C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D001381:Azepines; D008055:Lipids; D013876:Thiophenes; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase