Quasi-Irreversible Coordination to the Prosthetic Heme

This section focuses on inhibitors that are transformed by P450 enzymes into metabolic intermediate (MI) products that coordinate so tightly to the heme iron atom that they can be displaced only under unique experimental conditions. The two major classes of these inhibitors are compounds with a dioxymethylene function and nitrogen compounds, usually amines that are converted in situ to nitroso metabolites. A related mechanism is also partially responsible for the inhibition of P450 by 1,1-disubstituted hydrazines and acyl hydrazines. The anaerobic reductive coordination of halocarbons to the heme iron atom is discussed in Section 3.4 because the reaction is linked to destruction of the heme. 

The structural analogy between a carbene and carbon monoxide provides a ready explanation for the unusual 455-nm absorption maximum of the complexes. As already noted, a different complex is responsible for the absorption maximum at 

427 nm, perhaps a carbene complex in which the trans ligand, as in P420, is not a thiolate. A carbene complex also provides a ready rationale for the incorporation of oxygen from the medium into the carbon monoxide metabolite formed from the dioxymethylene bridge carbon (see below), and the observation that carbon monoxide formation is enhanced by electron-withdrawing sub-stituents. Water addition to the iron-coordinated carbene produces an iron-coordinated anion that should readily decompose into the observed catechol and carbon monoxide metabolites. A different but undefined mechanism is required to explain the incorporation of an atom of molecular oxygen into a fraction of the carbon monoxide  

Additional methylenedioxyphenyl compounds have been S5mthesized and their human isoform selectivity as mechanism-based inactivators evalu-ated. Their inactivating potential depends on the side-chain structure, with bulky side chains such as 1,4-benzothiazine inactivating some P450 enzymes but not others.  

It is noteworthy that the in vivo complexation of TAO to the heme of CYP3A enzymes stabilizes them and prolongs their half-lives in hepato-cytes . A consequence of this is that the 

---