Biology Reference
In-Depth Information
CYP2B or CYP3A, may be important in the metabolism of similar pesticide substrates
(
Kinsler et al., 1990
). Metabolic interactions involving enzyme induction and/or inhi-
bition are discussed in Chapter 7.
CYP-dependent reactions, as they involve pesticides, are considered in detail in
Chapter 5. A more mechanism-based classification of CYP-catalyzed xenobiotic oxida-
tions is that of
Guengerich and MacDonald (1984)
. They classified such reactions into
six general categories:
1.
Carbon hydroxylation: the formation of an alcohol at a methyl, methylene, or
methine position.
2.
Heteroatom release: the oxidative cleavage of the heteroatom part of a molecule
resulting from a hydroxylation adjacent to the heteroatom that generates a geminal
hydroxy heteroatom-substituted intermediate such as a carbinolamine, halohydrin,
hemiacetal, hemiketal, or hemithioketal. (This intermediate then collapses to release
the heteroatom and form a carbonyl compound.)
3.
Heteroatom oxygenation: the conversion of a heteroatom-containing substrate to
its corresponding heteroatom oxide as in the formation of
N
-oxides, sulfoxides, or
phosphine oxides.
4.
Epoxidation: the formation of oxirane derivatives of olefins or aromatic
compounds.
5.
Oxidative group transfer: a type of reaction that involves a 1,2-carbon shift of a group
with the concurrent incorporation of oxygen to form a carbonyl at the C1 position.
6.
Olefinic suicide destruction: inactivation of the heme of P450 by an enzyme
product.
Flavin-Containing Monooxygenase
The microsomal FMO was known for a number of years as an amine oxidase but was
subsequently shown to be also a sulfur oxidase and a phosphorous oxidase. Like CYP,
the FMO is a microsomal enzyme, a monooxygenase requiring NADPH and oxygen,
and exists as multiple isoforms in various tissues.
However, FMO, unlike CYP, catalyzes only oxygenation reactions, has more spe-
cific substrate requirements, and is not known to be subject to induction or inhibition
by xenobiotics, apart from competitive inhibition by alternate substrates (
Kulkarni and
Hodgson, 1984a,b; Ziegler, 1980
). The mechanism of catalysis is also distinct (
Figure
4.3
) in that electrons are transferred directly from NADPH and not via an NADPH-
reductase. Also, because the formation of the hydroperoxyflavin form of the enzyme
precedes interaction with the substrate, maximum velocity (
V
max
) for a particular FMO
isoform is constant for all substrates, although the Michaelis constant (
K
m
) can vary
from one substrate to another. CYP isoforms, on the other hand, show variations from
one substrate to another in both
V
max
and
K
m
. The FMO is found in highest levels in
the liver, but is also found in significant levels in the lung and kidney.
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