58
Biotransformations of Drugs and Chemicals
C
OH
S-enzyme
CH
3
H
NAD
+
NADH
NAD
+
NADH
C
CH
3
O
H
CH
3
O
H
Enzyme-SH
NAD
+
NADH
C
CH
3
O
OH
H
2
O
C
CH
3
O
S-enzyme
C
H
OH
CH
3
H
Fig. 4
Alcohol dehydrogenases catalyze
the reversible oxidation of alcohols to
aldehydes and ketones, as illustrated by
the oxidation of ethanol to acetaldehyde.
The oxidation of aldehydes to carboxylic
acids, such as that of acetaldehyde to
acetic acid, is catalyzed by aldehyde
dehydrogenases. The aldehyde reacts
with a thiol in the aldehyde
dehydrogenase to give an
enzyme-bound hemithioacetal
intermediate that is then oxidized to an
enzyme-bound thioester and Fnally
released by hydrolysis of the
thioester bond.
aldehyde and ketone reductases that em-
ploy NADPH as the reducing cofactor are
also involved in the reduction of carbonyl
compounds to alcohols. The direction of
the reaction catalyzed by alcohol dehydro-
genases is dictated by the redox balance
of the pyridine nucleotide pool and by
whether an alcohol or carbonyl compound
is the substrate, although a thermody-
namic equilibrium mixture of the alcohol
and carbonyl compound would be ob-
t
a
in
edw
e
r
ei
tn
o
tf
o
rth
ef
a
c
tth
a
tth
e
substrate and product are removed from
the solution by alternative metabolic re-
actions and the dynamic nature of the
circulatory and excretory systems.
Aldehydes are primarily oxidized by
NAD
+
-dependent aldehyde dehydroge-
nases (Fig. 4). A molybdenum-containing
enzyme related to xanthine oxidase may
also contribute to aldehyde oxidation, but
its physiological importance in the general
metabolism of xenobiotic aldehydes is un-
clear. Unlike the alcohol dehydrogenases,
thea
ldehydedehydrogenasesdono
ts
im
-
ply transfer a hydride from the aldehyde
substrate to the pyridine nucleotide cofac-
tor. The ┬▒rst step of the reaction is addition
of the aldehyde to an active site cysteine
thiol to give a hemithioacetal that is then
dehydrogenated by a hydride transfer to
an enzyme-bound thioester. Hydrolysis of
the thioester releases the acid metabolite
and regenerates the enzyme (Fig. 4). Be-
cause of the complexity of this mechanism,
aldehyde dehydrogenases catalyze the ox-
idation of aldehydes to acids but not the
reverse reaction. In effect, carboxylic acids
and xenobiotics with functionalities such
as amides and esters in which the carbon
has a comparable oxidation state are rarely
metabolically reduced.
Alcohol and aldehyde dehydrogenases
are the primary enzymes involved in the
metabolism of ethanol, the former catalyz-
ing the oxidation of ethanol to acetaldehyde
and the latter the conversion of acetalde-
hyde to acetic acid (Fig. 4). The oxidation
of ethanol to acetaldehyde can also be me-
diated by catalase and cytochrome P450,
but under normal conditions alcohol de-
hydrogenases are the principal catalysts
for this transformation. Genetic polymor-
phisms in the levels of both the alcohol
and aldehyde dehydrogenases are respon-
s
i
b
l
ef
o
rth
el
ow
e
rt
o
l
e
r
an
c
eo
fc
e
r
t
a
in
populations to the pharmacological ef-
fects of ethanol. Inhibition of acetaldehyde
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