Stereoselective Metabolism of Isoprothiolane and Its Sulfoxide in Rat Liver <i>in Vitro</i> and Rice Plants

Abstract

Enantiomers of isoprothiolane sulfoxide (diisopropyl 1-oxo-l, 3-dithiolan-2-ylidenemalonate) were resolved and separately analyzed both by chiral HPLC. The specific rotation was around + and-112° for each antipode. Isoprothiolane (diisopropyl l, 3-dithiolan-2ylidenemalonate) was easily oxidized by a rat liver 9000 g supernatant to produce its racemic sulfoxide, in which NADPH was an effective cofactor but NADH was not. The liver microsomes, however, preferentially formed its (+)-isomer in an enantiomeric excess of 38-43%. Phenobarbital (PB) increased the sulfoxidation activity of microsomes by 400% without any marked change in the enantiomeric excess. 3-Methylcholanthrene (3-MC) induced the microsomal activity more enantiomerically, forming isoprothiolane (+)-sulfoxide in an enantiomeric excess of 83%. Thus, 3-MC-induced microsomal enzyme(s) oxidize isoprothiolane to its (+)-sulfoxide more stereoselectively than PB-induced microsomal enzyme(s). The sulfoxidation of isoprothiolane by rice plants proceeded too slowly for the metabolite chirality to be analyzed. Both isoprothiolane (+)-and (-)-sulfoxides underwent rapid racemization by rat liver cytosol (105, 000 g supernatant) or rice plants, accompanied by the reduction to isoprothiolane.