Drug Metabolism in Drug Design and Development Basic Concepts and Practice

Mitchell, 1972), and care should be taken so as not to overlook possible
contributions of this enzyme. The C-4a-hydroperoxide is not a strong
electrophile, and the range of reaction is limited. In other flavoproteins, this
hydroperoxide can produce epoxides or Baeyer–Villiger products (Massey,
2000) but none have been reported for FMOs. FMOs can hydroxylate
activated phenyl groups, for example, phenols and anilines (Fig. 2.6)
(Frederick et al., 1982).

2.5.3 Monoamine Oxidase (MAO)

MAO oxidizes amines, particularly biogenic amines involved as neurotrans-
mitters (Cashman, 1997). Like FMO, this is a flavoprotein oxidase, but the
mechanism is different:

RCH 2 NH 2 þO 2 !RCHOþH 2 O 2 þNH 3

Two forms of MAO are known, A and B, which are slightly different. The
enzymes are found in the outer mitochondrial membrane of liver and some
neurogenic tissues.
The endogenous substrates of this enzyme are biogenic amines, for example,
dopamine and tryptamine, and MAO has been a target for inactivating drugs
(Van Houten et al., 1998). Although the enzyme had long been considered only
to use primary amines as substrates, an interesting discovery was the oxidation
ofN-methyl, 4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) to poison mitochon-
dria in the substantia nigra of the brain, yielding a Parkinson’s disease-type
syndrome (Chiba et al., 1985) (Fig. 2.7).

NADPH

E

NADP+

FADH 2

E

NADP+

FADH 2

O 2

E

NADP+

E FAD-4a-OOH

NADP+

FAD-4a-OOH

S

E

NADP+

FAD-4a-OH

E

NADP+

FAD

NADP+ E

FAD

O 2

S

SO

H 2 O

FIGURE 2.5 Catalytic cycle of FMOs.

22 OXIDATIVE, REDUCTIVE, AND HYDROLYTIC METABOLISM OF DRUGS