Fungal Metabolism of Phenolic and Nonphenolicp-Cymene-Related Drugs and Prodrugs. I. Metabolites of Thymoxamine
Abstract
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 asN-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.
Footnotes
-
Send reprint requests to: Dr. Robert Azerad, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, URA 400 CNRS, Université René Descartes, 45 rue des Saints-Pères, 75270-Paris Cedex 06, France.
-
This study was supported by the Institut de Recherches Chimiques et Biologiques Appliquées (Vicq, France), Laboratoires Fournier (Dijon, France), and partially by an European Communities Programme “Human Capital and Mobility: Biooxygenations” (Contract ERBCHRXCT930259). This work was completed by C. Moussa in partial fulfillment of her Doctorate of Science degree.
-
↵2 All strains tested in the usual biotransformation conditions invariably reduced thymoquinone4 into thymohydroquinone 10.
- Abbreviations used are::
- DAT
- desacetylthymoxamine
- DMAT
- N-desmethyl-desacetylthymoxamine
- CI
- chemical ionization
- Received July 2, 1996.
- Accepted December 10, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|