Chemical reactivity considerations in the metabolism of N-heteroaromatics

Enzymic carbon hydroxylations in N-heteroaromatics may involve either an electrophilic activated oxygen species (oxene), or a nucleophile (hydroxyl ion, OH-). A consideration of the chemical reactivities of ring systems often allows tentative predictions of likely reaction products with appropriate enzyme systems. e.g. microsomal cytochrome P-450, or cytosolic molybdenum hydroxylases. Pyrroles and related pi-excessive N-heteroaromatics are substrates for electrophilic enzymic ring hydroxylations mediated by cytochrome P-450, but the acidic ring nitrogen in pyrroles is not normally a site for metabolic attack. Pyridines and related pi-deficient N-heteroaromatics are substrates for nucleophilic enzymic ring hydroxylations mediated by molybdenum hydroxylases. The nucleophilic nitrogen in such rings can also be a site for metabolism, affording N-oxides or quaternary N-conjugates as metabolites.