The Mitochondrial Amidoxime Reducing Component (mARC): Involvement in Metabolic Reduction of N‐Oxides, Oximes and N‐Hydroxyamidinohydrazones

Abstract The mitochondrial amidoxime reducing component (mARC) is a molybdenum‐containing enzyme and capable of reducing N‐hydroxylated structures such as amidoxime prodrugs. In this study, we tested the involvement of mARC in the reduction of N ‐oxides (amitriptyline‐ N ‐oxide, nicotinamide‐ N ‐oxide), oximes (( E )‐/( Z )‐2,4,6‐trimethylacetophenonoxime) and a N ‐hydroxyamidinohydrazone (guanoxabenz). All groups are reduced by mARC proteins, and the enzymes are therefore involved in the interconversion of N‐oxygenated metabolites originating from cytochrome P450s and flavin‐containing monooxygenases. In addition, these structures open up further options for serving as prodrugs. Thus, with respect to these reactions, testing of candidates with N‐oxygenated structures should not solely be carried out in microsomal enzyme sources but as well in mitochondria. However, differences in the reduction of oximes and N ‐oxides between the two isoforms, namely mARC1 and mARC2, were detectable; N ‐oxides are exclusively reduced by mARC1. We therefore assume differences between the so far unknown 3D structures of the two proteins.