RT Journal Article
SR Electronic
T1 The Involvement of the Mitochondrial Amidoxime Reducing Component (mARC) in the Reductive Metabolism of Hydroxamic Acids
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1396
OP 1402
DO 10.1124/dmd.118.082453
VO 46
IS 10
A1 Carsten Ginsel
A1 Birte Plitzko
A1 Danilo Froriep
A1 Diana A. Stolfa
A1 Manfred Jung
A1 Christian Kubitza
A1 Axel J. Scheidig
A1 Antje Havemeyer
A1 Bernd Clement
YR 2018
UL http://dmd.aspetjournals.org/content/46/10/1396.abstract
AB The mitochondrial amidoxime reducing component is a recently discovered molybdenum enzyme in mammals which, in concert with the electron transport proteins cytochrome b5 and NADH cytochrome b5 reductase, catalyzes the reduction of N-oxygenated structures. This three component enzyme system plays a major role in N-reductive drug metabolism. Belonging to the group of N-hydroxylated structures, hydroxamic acids are also potential substrates of the mARC-system. Hydroxamic acids show a variety of pharmacological activities and are therefore often found in drug candidates. They can also exhibit toxic properties as is the case for many aryl hydroxamic acids formed during the metabolism of arylamides. Biotransformation assays using recombinant human proteins, subcellular porcine tissue fractions as well as human cell culture were performed. Here the mARC-dependent reduction of the model compound benzhydroxamic acid is reported in addition to the reduction of three drugs. In comparison with other known substrates of the molybdenum depending enzyme system (e.g., amidoxime prodrugs) the conversion rates measured here are slower, thereby reflecting the mediocre metabolic stability and oral bioavailability of distinct hydroxamic acids. Moreover, the toxic N-hydroxylated metabolite of the analgesic phenacetin, N-hydroxyphenacetin, is not reduced by the mARC-system under the chosen conditions. This confirms the high toxicity of this component, as it needs to be detoxified by other pathways. This work highlights the need to monitor the N-reductive metabolism of new drug candidates by the mARC-system when evaluating the metabolic stability of hydroxamic acid-containing structures or the potential risks of toxic metabolites.