BIOTRANSFORMATION OF CHLORPROMAZINE AND METHDILAZINE BY CUNNINGHAMELLA-ELEGANS

When tested as a microbial model for mammalian drug metabolism, the fi lamentous fungus Cunninghamella elegans metabolized chlorpromazine and methdilazine within 72 h. The metabolites were extracted by chlorofor m, separated by high-performance liquid chromatography, and characteri zed by proton nuclear magnetic resonance, mass, and UV spectroscopic a nalyses. The major metabolites of chlorpromazine were chlorpromazine s ulfoxide (36%), N-desmethylchlorpromazine (11%), N-desmethyl-7-hydroxy chlorpromazine (6%), 7-hydroxychlorpromazine sulfoxide (5%), and chlor promazine N-oxide (2%), all of which have been found in animal studies . The major metabolites of methdilazine were 3-hydroxymethdilazine (35 %), methdilazine sulfoxide (30%), methdilazine N-oxide (4%), phenothia zine (3%), and 2-hydroxymethdilazine (3%). O-18(2) labeling experiment s indicated that the oxygen atoms in methdilazine sulfoxide, methdilaz ine N-oxide, and 3-hydroxymethdilazine were all derived from molecular oxygen. The production of methdilazine sulfoxide and 3-hydroxymethdil azine was inhibited by the cytochrome P-450 inhibitors metyrapone and proadifen. An enzyme activity for the sulfoxidation of methdilazine wa s found in microsomal preparations of C. elegans. These experiments su ggest that the sulfoxidation and hydroxylation of methdilazine and chl orpromazine by C. elegans are catalyzed by cytochrome P-450.