378
chapter 18
Lipids I: Fatty Acids and Eicosanoids
barbiturates). Peroxisom al catalase catalyzes the reaction:
C H
3
C H
2
O H + H
2
0
2
-+ C H
3
CH O + 2H 20
The
Km
for this catalase and for the m ixed-function o x -
idase is about 10 m M /L . T he extent to w hich these tw o
enzym es m etabolize ethanol is not known.
A cetaldehyde is converted to acetate in the liver
by N A D + -linked aldehyde dehydrogenases, one in the
cytosol (
Km
= 1 m M /L ) and another in m itochondria
(Km =
0.01 m M /L ):
C H
3
CH O + N A D + + H 20
C H
3
C O O “ + N A D H + 2H +
Disulfiram (tetraethylthiuram disulfide)
HSC^
^C 2Ft5
N — C — S — S — C — N
/ 1 1
11
\
H
5
C
2
S
S
C
2
HS
causes irreversible inactivation o f these aldehyde dehydro-
genases by reacting with sulfhydryl groups, with a buildup
o f acetaldehyde that produces the acetaldehyde syndrom e
(vasodilation, intense throbbing, pulsating headache, res-
piratory difficulties, copious vom iting, sw eating, thirst,
hypotension,
vertigo, blurred vision, and confusion).
Disulfiram by itself is relatively nontoxic. It is used in
the treatment o f chronic alcoholism but does not cure it.
Disulfiram provides a w illing patient with a deterrent to
consum ption o f alcohol. A shorter acting reversible in-
hibitor o f aldehyde dehydrogenase is calcium carbim ide,
w hich causes accum ulation o f acetaldehyde and unpleas-
ant sym ptom s. Thus, calcium carbim ide can also be used
as a deterrent to alcohol consum ption.
Sym ptom s sim ilar to the disulfiram -ethanol reaction
occur in high proportion in certain ethnic groups (e.g.,
A sians and N ative A m ericans) w ho are extrem ely sen-
sitive to ethanol consum ption. The ethanol sensitivity in
these populations is accom panied by a higher acetalde-
hyde steady-state concentration in the blood, w hich may
be due to a rapid rate o f form ation o f acetaldehyde by alco-
hol dehydrogenase or to a decreased rate o f its rem oval by
aldehyde dehydrogenase. Both o f these dehydrogenases
are present in several isozym e form s and exhibit extensive
polym orphism am ong racial groups. A n alcohol dehydro-
genase variant found in the ethanol-sensitive populations
has a relatively higher rate o f activity at p hysiological pH
and m ay account for m ore rapid oxidation o f ethanol to
acetaldehyde. H ow ever, a m ore important cause o f ac-
etaldehyde accum ulation appears to be deficiency o f an
isozym e o f aldehyde dehydrogenase, w hich has a low
Km
for acetaldehyde. Thus, the cause o f ethanol sensitivity
m ay be im paired rate o f rem oval o f acetaldehyde rather
than its excessive form ation. Individuals w ho are predis-
posed to ethanol sensitivity should avoid ethanol intake in
any form.
A cetate produced from ethanol is converted to acetyl-
C oA by acetyl-C oA synthase in hepatic and extrahepatic
tissues.
C H
3
COO
+ ATP4“ + C oA SH - *
C H
3
C O SC
0
A + A M P 2“ + PP2“
A cetyl-C oA is oxid ized in the T C A cycle and is used in
liver and adipose tissue for biosynthesis o f fatty acids and
triacylglycerol.
A lcoh olism affects about 10% o f the drinking popu-
lation and alcohol (ethanol) abuse has been im plicated
in at least 20% o f adm issions to general hospitals. This
chronic disease exhibits high m ortality due to a w ide va-
riety o f factors. Ethanol produces effects in virtually ev-
ery organ system . The biochem ical effects o f ethanol are
due to increased production o f N A D H that decreases the
[N A D + ]/[N A D H ] ratio in the cytoplasm o f liver cells at
least tenfold from the normal value o f about 1000. In-
creased production o f lactate and inhibition o f gluconeo-
gen esis (Chapter 15) result. The hyperuricem ia associated
w ith ethanol consum ption has been attributed to acceler-
ated turnover o f adenine nucleotides and their catabolism
to uric acid (Chapter 27). A lcoh ol increases hepatic fatty
acid and triacylglycerol synthesis and m obilization o f fat
from adipose tissue, w hich can lead to fatty liver, hep-
atitis, and cirrhosis. T hese effects are com plicated by a
deficiency o f B vitam ins and protein.
A lcohol increases the plasm a level o f V L D L and o f
H D L cholesterol (Chapter 20).
M any
actions
o f ethanol
m ay
be
attributed to
a
m em brane-disordering effect. C hanges in m em brane flu-
idity can affect m em brane-bound en zym es (e.g., N a+ , K + -
ATPase, adenylate cyclase) and phospholipid architecture.
A lcohol also affects several neurotransmitter system s in
the brain. T hese include dopam ine (m ediates pleasur-
able effects), y-am inobutyric acid (G A B A ), glutam ate,
serotonin, adenosine, norepinephrine, and opioid pep-
tides. Potential drug therapy for alcohol dependence con -
sists o f the use o f antagonists and agonists o f alcohol
affected neurotransmitter system s.
For exam ple,
nal-
trexone, a /r-opioid antagonist, inhibits alcohol-induced
dopam ine release, thus m inim izing the pleasurable effect
o f alcohol and reducing the desire to consum e alcohol.
A nother drug, acam prosate, reduces the craving for alco-
hol presum ably by an agonist activity at G A B A receptors
