Drug Metabolism in Drug Design and Development Basic Concepts and Practice

2.6.2 NADPH-P450 Reductase

The normal functions of this flavoprotein are to transfer electrons
from NADPH to P450 (and to heme oxygenase, the enzyme that degrades
heme, after breakdown of proteins to release free heme, to biliverdin and
CO). However, the enzyme can react with oxidized molecules, in what is
probably generally a second-order reaction, to reduce them. Some of the
substrates for reduction overlap with the nitrogen-containing molecules
listed above under P450. In the scheme shown in Fig. 2.8, P450 1A2
catalyzes the oxidation steps and NADPH-P450 reductase catalyzes the
reduction.
Because of the nature of the electron transfer processes in the flavins of
this protein, it can catalyze either 1eor 2ereductions. As pointed out
later under the heading of NAD(P)H–quinone reductase, this is an important
issue in that 1ereduction processes can generate radicals. For instance,
NADPH-P450 reductase reduces the herbicide paraquat (methyl viologen)
to a radical, which rapidly reacts with O 2 to form superoxide anion
(Fig. 2.9).

RNH 2 RNHOH RN=O

P450/NPR P450/NPR

NPR NPR

NADPH NADPH

NADPH NADPH

NADP+ NADP+

NADP+ NADP+

FIGURE 2.8 Abortive redox cycling and oxidation of NADPH in a system involving a
heterocyclic arylamine (Kim et al., 2004). NPR = NADPH-P450 reductase.

NADPH

NADP+

Paraquat

Paraquat+

O 2 –

O 2

NADPH-

cytochrome

P450

reductase

FIGURE 2.9 Abortive redox cycling, oxidation of NADPH, and superoxide
production with paraquat.

REDUCTION 27