Hydride-Meisenheimer metabolism in mammals - scope of an overlooked biotransformation pathway

Nitroaromatics are used for various industrially relevant products such as pharmaceuticals, pesticides, and explosives. Their unique reactivity properties render them susceptible to specific biotransformations. While nitro reduction is common and has been extensively studied in micro- and higher organisms, the biotransformation to Hydride-Meisenheimer complexes (HMC) has rarely been detected and is described mostly in microorganisms. The detection of HMC for the drug candidate BTZ-043 in mammals, including humans, suggests that mammalian HMC formation may have broader relevance for other nitroaromatic compounds. With a recently developed mammalian whole-cell HMC biotransformation assay, our systematic study provides the first insights into structural requirements for mammalian HMC biotransformation of nitroaromatics. We detected HMC formation for several compound classes, broadening the substrate scope and providing a strong rationale for the relevance of HMC formation for the pharmacokinetics of some nitroaromatic pharmaceuticals, as well as for pharmacokinetic and toxicological assessments of a variety of substances of industrial or environmental origin. Structural analysis of HMC-susceptible compounds indicated that molecular fingerprint similarity did not distinguish HMC-forming compounds; instead, the electrostatic potential at individual carbon atoms was found to be a suitable quantum-mechanics-derived parameter to predict metabolism susceptibility.