title: 19-Azasqualene-2,3-epoxide and its N-oxide: metabolic fate and inhibitory effect on sterol biosynthesis in Saccharomyces cerevisiae.
abstract: 19-Azasqualene-2,3-epoxide was more inhibitory than the corresponding N-oxide against 2,3-oxidosqualene cyclase (OSC) solubilized from Saccharomyces cerevisiae (IC50 7+/-2 and 25+/-5 microM, respectively). Both compounds showed a reversible, noncompetitive-type inhibition on solubilized OSC. Different inhibitory properties between the compounds were especially evident when measuring [14C]acetate incorporation into nonsaponifiable lipids extracted from treated cells. In cells treated with 19-azasqualene-2,3-epoxide at 30 microM, the radioactivity associated with the oxidosqualene fraction, which was negligible in the controls, rose to over 40% of the nonsaponifiable lipids, whereas it remained at a slightly appreciable level in cells treated with the N-oxide derivative under the same conditions. 19-Azasqualene-2,3-epoxide was also more effective than the N-oxide as a cell growth inhibitor (minimal concentration of compound needed to inhibit yeast growth: 45 and >100 microM, respectively). The two inhibitors underwent different metabolic fates in the yeast: while 19-azasqualene-2,3-epoxide did not undergo any transformation, its N-oxide was actively reduced to the corresponding amine in whole and in "ultrasonically stimulated" cells. The N-oxide reductases responsible for this transformation appear to be largely confined within the microsomal fractions and require NADPH for their activity. A possible relationship between the inhibitory properties of the two compounds and their metabolic fates is discussed.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Torino, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Milla
authors.forename: F
authors.initials: F
authors.lastname: Viola
authors.forename: M
authors.initials: M
authors.lastname: Ceruti
authors.forename: F
authors.initials: F
authors.lastname: Rocco
authors.forename: L
authors.initials: L
authors.lastname: Cattel
authors.forename: G
authors.initials: G
authors.lastname: Balliano
mesh_terms: D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004852:Epoxy Compounds / Q000494:pharmacology*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013185:Squalene / Q000031:analogs & derivatives* / Q000494:pharmacology; D013261:Sterols / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
chemical_list: C122127:19-azasqualene-2,3-epoxide; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D013261:Sterols; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase