MICROBIAL MODELS OF MAMMALIAN METABOLISM - FUNGAL METABOLISM OF PHENOLIC AND NONPHENOLIC P-CYMENE-RELATED DRUGS AND PRODRUGS .1. METABOLITES OF THYMOXAMINE

This study was undertaken to validate the use of microbial biotransfor mation systems for drug metabolism studies. Thymoxamine 1 was rapidly hydrolyzed to desacetylthymoxamine (DAT)2 by numerous fungi. Other kno wn animal metabolites, such as N-desmethyl-desacetylthymoxamine 3 and desacetylthymoxamine-O-sulfate 6, were produced from DAT by Mucor roux ii and Mortierella isabellina. DAT-N-oxide 5, a putative animal micros omal metabolite, was also produced by M. isabellina. In addition, a fe w strains (such as Actinomucor elegans, Mucor hiemalis, and Mucor jans senii) produced a glycosylated metabolite that was identified by high- resolution H-1- and C-13-NMR, MS, and enzymatic hydrolysis as the corr esponding sopropyl-2-methyl-phenyl]-1-beta-D-glucopyranoside 7. A simi lar glucosylation reaction was observed when thymohydroquinone 10 was incubated with A. elegans. Several strains were able to produce transi ently thymohydroquinone from DAT-N-oxide 5, possibly through a beta-el imination mechanism.