title: In vitro metabolism of pyripyropene A and ACAT inhibitory activity of its metabolites.
abstract: Pyripyropene A (PPPA, 1) of fungal origin, a selective inhibitor of acyl-CoA:cholesterol acyltransferase 2 (ACAT2), proved orally active in atherogenic mouse models. The in vitro metabolites of 1 in liver microsomes and plasma of human, rabbit, rat and mouse were analyzed by ultra fast liquid chromatography and liquid chromatography/tandem mass spectrometry. In the liver microsomes from all species, successive hydrolysis occurred at the 1-O-acetyl residue, then at the 11-O-acetyl residue of 1, while the 7-O-acetyl residue was resistant to hydrolysis. Furthermore, dehydrogenation of the newly generated 11-alcoholic hydroxyl residue occurred in human and mouse-liver microsomes, while oxidation of the pyridine ring occurred in human and rabbit liver microsomes. On the other hand, hydrolysis of the 7-O-acetyl residue proceeded only in the mouse plasma. These data indicated that the in vitro metabolic profiles of 1 have subtle differences among animal species. All of the PPPA metabolites observed in liver microsomes and plasma markedly decreased ACAT2 inhibitory activity. These findings will help us to synthesize new PPPA derivatives more effective in in vivo study than 1.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsuda
authors.affiliation: 1] Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan [2] Section on Lipid Sciences, Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Taichi
authors.initials: T
authors.lastname: Ohshiro
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohtawa
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Nagamitsu
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D005260:Female; D006801:Humans; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism*; D011725:Pyridines / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000378:metabolism*; D013045:Species Specificity; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D053719:Tandem Mass Spectrometry / Q000379:methods*; D000097587:Sterol O-Acyltransferase 2
chemical_list: D011725:Pyridines; D012717:Sesquiterpenes; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C082792:pyripyropene A