Drug Metabolism in Drug Design and Development Basic Concepts and Practice

xenobiotics, with about five dominant in drug metabolism (Fig. 2.1b). The
functions of1/4 of the P450s are still largely uncharacterized, although these
‘‘orphans’’ are not expected to have major roles in drug metabolism
(Guengerich, 2005; Guengerich et al., 2006).
The generalized catalytic cycle for P450s is shown in Fig. 2.2. Steps 1–3, and
9 can be studied but the details of steps 4–8 are more difficult to observe directly
(Schlichting et al., 2000), or are inferred from physical organic considerations.
Electrons are transferred from an auxiliary enzyme, NADPH-P450 reductase, or
possibly cytochromeb 5 in some cases. The reaction chemistry can generally be
rationalized in the context of processes involving FeO3+(formally FeV=Oor
FeIV= O plus a porphyrin radical) (Ortiz de Montellano and De Voss, 2005).
Alternate dioxygen complexes (FeO 2 þ;FeO 2 H^2 þ) (Chandrasena et al., 2004) and
multiple forms of FeO3+chemistry (Shaik et al., 2005) have been proposed to
contribute to P450 reactions. However, the dominant factors in determining
catalytic selectivity are generally agreed to be the interactions of the substrate
with the amino acids of the protein and, within the context of a set of similar
compounds (Burka et al., 1985; Macdonald et al., 1989), the ease of abstraction
of hydrogen atoms or nonbinding electrons. Structures of some P450–substrate
complexes have now become available and are useful, although even with these
there is an issue of whether the juxtaposition is that relevant to the step in which
oxidation occurs (Fig. 2.2).
Some of the major types of P450 reactions are shown in Fig. 2.3. These have
common chemistry and can be rationalized in terms of odd-electron
oxidations. The basic mechanisms can be extended to a variety of other
reactions, which are treated in more detail elsewhere (Guengerich, 2001; Ortiz

Fe3+ RH

FeII-OOH

RH

FeO3+RH

Fe3+ ROH

1e-

1e-

1

2

3

5 4

6

7

8

9

NADPH-P450 reductasered

NADPH-P450 reductaseox

NADPH-P450 reductaseox

NADPH-P450 reductasered

Fe3+

Fe2+RH

Fe2+-O 2 RH

Fe2+-O 2 - RH

FeOH3+R•

H+

-ROH RH

O 2

-H 2 O

FIGURE 2.2 Generalized catalytic cycle for P450 oxidations. (Adapted with
permission from Guengerich, 2001).

OXIDATION ENZYMES 19