Biotransformations of Drugs and Chemicals
53
very same properties that militate against
its excretion.
The
primary
purpose
of
xenobiotic
metabolism
is
to
convert
lipophilic
compounds to polar materials that can
be
eliminated.
For
this
reason,
the
highest concentrations of enzymes of drug
metabolism are found at sites that are
portals of entry into the organism, such as
the lungs, intestine, and liver of mammals.
It is instructive in this context to consider
the
example
of
compounds,
typi±ed
by manmade polyhalogenated aromatic
hydrocarbons, that are poorly metabolized
by the enzymes evolved for the metabolism
of natural products. Compounds such
as
the
highly
halogenated
biphenyls
accumulate
in
adipose
tissues
and
a
major
fraction
remains
there
for
essentially the lifetime of the individual.
This accumulation of lipophilic, poorly
metabolized compounds in fatty tissues is
the basis for the well-known concentration
of xenobiotics in natural food chains.
2
Classifcation and Properties oF Enzymes oF
Xenobiotic Metabolism
The enzymes of drug metabolism pre-
dominantly catalyze oxidation/reduction,
hydrolysis, and conjugation reactions, al-
though there is some ambiguity in as-
signing enzymes to the drug-metabolizing
system. For organizational purposes, the
redox and hydrolytic enzymes are consid-
ered to be responsible for early stages of
xenobiotic metabolism and are known as
Phase I enzymes. The conjugative en-
zymes are usually responsible for the
later transformations in a metabolic se-
quence
and
are
known
as
Phase
II
enzymes. This classi±cation is arti±cial
because Phase II conjugation reactions
need not be preceded by Phase I reac-
tions, although it is true that Phase I
redox or hydrolytic reactions usually oc-
cur before the Phase II conjugations that
make compounds highly polar. Phase I
xenobiotic metabolism is largely catalyzed
by
cytochrome
P450
and
flavoprotein
monooxygenases, monoamine oxidases,
alcohol
and
aldehyde
dehydrogenases,
esterases and amidases, and epoxide hy-
drolases. The enzymes involved in Phase
II
metabolism
are
primarily
the
glu-
curonyl transferases, sulfotransferases,
N
-
acyl transferases, methylases, and glu-
tathione transferases. Despite their in-
volvement
in
drug
metabolism,
some
members of both the Phase I and Phase II
classes of enzymes are primarily or exclu-
sively involved in the processing of endoge-
nous substrates. Furthermore, many drugs
resemble endogenous substances and are
subject to metabolism by the more spe-
cialized enzymes involved in processing
of endobiotics. For example, fatty acid
β
-
oxidation, a pathway for the catabolism
of endogenous fatty acids, also degrades
xenobiotic alkyl chains that terminate in
carboxyl groups.
Some
generalizations
can
be
made
concerning the properties of enzymes
that
are
primarily
devoted
to
xenobi-
otic metabolism. In contrast to enzymes
that process endobiotics, the enzymes of
drug metabolism have broad substrate
speci±cities and are stereoselective rather
than stereospeci±c. There are not many
classes of drug-metabolizing enzymes, but
each class encompasses multiple enzyme
forms. This combination of loose sub-
strate speci±city and enzyme multiplicity
provides the flexibility required to metabo-
lize the diversity of natural and manmade
substances to which organisms are rou-
tinely exposed. The ability to deal with
speci±c xenobiotics is enhanced by the
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