The mechanism of cytochrome P450-catalysed drug oxidations

Abstract

Most compounds involved in the metabolism of cells, organs and organisms are hydrophilic in nature, possessing polar groups capable of undergoing a variety of metabolic reactions. Lipophilic molecules, like steroids or the fat-soluble vitamins, are in the minority. These latter compounds consist, in substantial part, of aromatic or alicyclic rings and/or aliphatic side-chains. These hydrocarbon groups are metabolically rather inert and in fact only one group of enzymes, the mono-oxygenases, can attack aromatic or aliphatic C—H bonds. Monooxygenases use molecular oxygen and two electrons from an external donor to introduce an oxygen atom into organic substrates according to the equation (Mason, 1957):

$$$$

where RH represents substrate and DH₂ represents reduced electron donor. Such enzymes play an important role in the formation and transformation of steroids, bile acids, amino acids or vitamins (Ullrich, 1972). Micro-organisms using lipophilic compounds as the sole carbon source rely on the presence of mono-oxygenases for the initial oxidation of the substrate to alcohols, which can be further oxidised with concomitant production of chemical energy.