9-azasqualene-2,3-epoxide and its N-oxide: Metabolic fate and inhibitory effect on sterol biosynthesis in Saccharomyces cerevisiae

19-Azasqualene-2,3-epoxide was more inhibitory than the corresponding N-oxi de against 2,3-oxidosqualene cyclase (OSC) solubilized from Saccharomyces c erevisiae (IC50 7 +/- 12 and 25 +/- 5 mu M, respectively). Both compounds s howed a reversible, noncompetitive-type inhibition on solubilized OSC. Diff erent inhibitory properties between the compounds were especially evident w hen measuring [C-14]acetate incorporation into nonsaponifiable lipids extra cted from treated cells. In cells treated with 19-azasqualene-2,3-epoxide a t 30 mu M, the radioactivity associated with the oxidosqualene fraction, wh ich was negligible in the controls, rose to over 40% Of the nonsaponifiable lipids, whereas it remained at a slightly appreciable level in cells treat ed 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 inhibit or (minimal concentration of compound needed to inhibit yeast growth: 45 an d >100 mu M, respectively). The two inhibitors underwent different metaboli c 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 th e microsomal fractions and require NADPH for their activity. A possible rel ationship between the inhibitory properties of the two compounds and their metabolic fates is discussed.