Microbial models of mammalian metabolism : Fungal metabolism of phenolic and nonphenolic p-cymene-related drugs and prodrugs. I. Metabolites of thymoxamine

This study was undertaken to validate the use of microbial biotransformation systems for drug metabolism studies. Thymoxamine 1 was rapidly hydrolyzed to desacetylthymoxamine (DAT) 2 by numerous fungi. Other known animal metabolites, such as N -desmethyl-desacetylthymoxamine 3 and desacetylthymoxamine- O -sulfate 6, were produced from DAT by Mucor rouxii and Mortierella isabellina . DAT- N -oxide 5, a putative animal microsomal metabolite, was also produced by M. isabellina . In addition, a few strains (such as Actinomucor elegans, Mucor hiemalis , and Mucor janssenii ) produced a glycosylated metabolite that was identified by high-resolution1H- and 13C-NMR, MS, and enzymatic hydrolysis as the corresponding [4-(2-dimethylaminoethoxy)-5-isopropyl-2-methyl-phenyl]-1-β-d-glucopyranoside 7. A similar glucosylation reaction was observed when thymohydroquinone 10 was incubated with A. elegans . Several strains were able to produce transiently thymohydroquinone from DAT- N -oxide 5, possibly through a β-elimination mechanism.