Cytochrome P450

The cytochrome P450 system can carry out a variety of oxidation reactions as listed in Table 7.2.

The overall scheme for these reactions is the insertion of a single oxygen atom into the drug molecule. Current views indicate that the chemistry of cytochrome P450 is radical by nature.

The mechanism of cytochrome P450 catalysis is probably constant across the system. It is determined by the ability of a high valent formal (FeO)3+ species to carry out one-electron oxidations through the abstraction of hydrogen atoms or electrons. The resultant substrate radical can then recombine with the newly created hydroxyl radical (oxygen rebound) to form the oxidized metabolite. Where a heteroatom is the (rich) source of the electron more than one product is possible. There can be direct recombination to yield the heteroatom oxide or radical relocalization within the

Tab. 7.2 Reactions performed by the cytochrome P450 system.

Reaction

Product

Typical example

Aromatic hydroxylation

Phenyl to phenol

Phenytoin

Aliphatic hydroxylation

Methyl to carbinol

Ibuprofen

N-dealkylation

Tertiary to secondary amine

Lidocaine

O-dealkylation

Ether to alcohol

Naproxen

S-dealkylation

Thioether to thiol

6-methylthiopurine

N-oxidation

Pyridine to pyridine N-oxide

Voriconazole

S-oxidation

Sulphoxide to sulphone

Omeprazole

Alcohol oxidation

Alcohol to carboxylic acid

Losartan

Fig. 7.1 Heteroatom oxidation of drugs by cytochrome P450 leading to heteroatom oxides or dealkylation products.

,N—CH2OH

substrate to a carbon and oxidation of this function to form the unstable carbinol and ultimately heteroatom dealkylation. A possible reaction sequence is illustrated as Figure 7.1.

Many of the investigations into the enzymology of cytochrome P450 over the previous 20 years have focused on the pathway that generates this reactive species as illustrated in Figure 7.2 particularly the donation of electrons and protons to yield the (FeO)3+ substrate complex which is the oxidizing species. As part of the cycle substrate binds to the enzyme as an initial step before the addition of electrons and molecular oxygen. The final stage of the cycle is the actual attack of the (FeO)3+ species on the substrate.

key stages of substrate interaction.

The critical points of the cycle involving substrate-enzyme interactions are illustrated in Figure 7.2 and explored below:

a) The initial binding of the substrate to the CYP which causes a change in the spin state of the haem iron eventually resulting in the formation of the (FeO)3+-sub-strate complex. This is obviously a key substrate-protein interaction and depends on the actual 3D-structure of the substrate and the topography of the active site.

Chemic metabol

Fig. 7.2 Cytochrome P450 cycle showing the

Fig. 7.2 Cytochrome P450 cycle showing the

However, it cannot be assumed that this initial binding is the same as the final conformation that the protein and substrate adopt during actual substrate attack. b)The final stages of the cycle, when the geometry and chemical reactivity of this complex determine the structure of the metabolite produced. Analysis of the literature indicates that three major forms of CYPs are involved in the metabolism of pharmaceuticals in man: CYP2D6, CYP2C9 and CYP3A4, CYP1A2, CYP2C19 and CYP2E1 are also involved, but this involvement is much less extensive. The catalytic selectivity of the major CYPs has been reviewed [1].

Was this article helpful?

0 0

Post a comment