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22553–22557, 2002
© 2002 by The American Society for Biochemistry and Molecular Biology, Inc. Printed in U.S.A.
Substantial evidence indicates that one consequence the adult to control epithelial cell differentiation (13) and to
of alcohol intoxication is a reduction in retinoic acid provide some brain functions such as spatial learning and
(RA) levels. Studies on the mechanism have shown that memory (14, 15) and motor skills (16).
chronic ethanol consumption induces P450 enzymes Retinoid activation is performed by enzymes that first oxi-
that increase RA degradation, thus accounting for much dize retinol to retinal followed by oxidation of retinal to RA.
but not all of the observed decrease in RA. A reduction Many of the retinoid-metabolizing enzymes identified in vitro
in RA synthesis may also be involved as ethanol compet- are members of the same families of alcohol- and aldehyde-
itively inhibits retinol oxidation catalyzed by alcohol metabolizing dehydrogenases that oxidize ethanol to acetalde-
dehydrogenase (ADH) in vitro. This may be important hyde and acetaldehyde to acetic acid (i.e. alcohol dehydrogen-
during acute ethanol intoxication and may contribute to
ase (ADH) and aldehyde dehydrogenase (ALDH), respectively)
adverse retinol/ethanol drug interactions. Here we have
(17). Deactivation of RA by oxidation to more polar metabolites
examined mice for the effect of either acute ethanol
intoxication or Adh1 gene disruption on RA synthesis can be performed by various cytochrome P450 enzymes (18 –
and degradation. RA produced following a dose of reti- 20). Thus, the steady-state level of RA is dependent upon the
nol (50 mg/kg) was reduced 87% by pretreatment with an activities of both synthesizing and degrading enzymes.
intoxicating dose of ethanol (3.5 g/kg). RA produced in It has been reported that chronic ethanol treatment of rats
Adh1-null mutant mice following a 50-mg/kg dose of ret- leads to a reduction in RA levels in liver and serum and that
inol was reduced 82% relative to wild-type mice, thus this may contribute to ethanol-induced liver carcinogenesis
similar to wild-type mice pretreated with ethanol. Re- (21). Further studies on the mechanism have indicated that
duced RA production was associated with increased ret- much, but not all, of the decrease in RA levels during chronic
inol levels in both ethanol-treated wild-type mice and ethanol treatment can be attributed to an increase in RA deg-
Adh1-null mutant mice, indicating reduced clearance of radation by ethanol-inducible CYP2E1, a P450 that was shown
the retinol dose. RA degradation following a dose of RA to metabolize RA to more polar metabolites (22). However, this
(10 mg/kg) was increased only 42% by ethanol pretreat- may not be the case for acute ethanol treatment as it takes days
ment (3.5 g/kg) and only 26% in Adh1-null mutant mice to weeks for CYP2E1 activity to be induced by ethanol (23).
relative to wild-type mice. These findings demonstrate Thus, the mechanism whereby ethanol reduces RA levels may
that the reduced RA levels observed during acute reti- be different depending on whether ethanol administration is
nol/ethanol drug interaction are due primarily to a de-
acute or chronic.
crease in ADH-catalyzed RA synthesis and secondarily
It has been hypothesized that ethanol may reduce RA syn-
to an increase in RA degradation.
thesis by acting as a competitive inhibitor of ADH-catalyzed
retinol oxidation (24, 25). Mouse embryos treated acutely with
ethanol have reduced levels of RA, which may be a contributing
Vitamin A (retinol) is metabolized to retinoic acid (RA),1 factor in the pathogenesis of fetal alcohol syndrome (26). Five
which serves as a ligand for nuclear retinoid receptors essential classes of ADHs are known to exist in humans and mice (27).
for growth and development of chordate animals (1, 2). Reti- Studies on purified human ADH1 and ADH4 have shown that
noid signaling influences pattern formation during the devel- these enzymes are direct targets of ethanol action because
opment of several organs including the central nervous system ethanol can competitively inhibit their abilities to catalyze
(3–5), limb buds (6 – 8), and eye (9). Also, RA controls epithelial/ retinol oxidation with Ki values of ⬃0.04 –3.8 mM for ADH1 and
mesenchymal inductive interactions during organogenesis of 6 –12 mM for ADH4 (28 –30). These Ki values are well within
the urinary and respiratory tracts (10 –12), and RA is needed in the range of blood alcohol concentrations achieved by moderate
or binge drinkers (31), and alcoholics have much higher blood
* This work was supported by National Institutes of Health Grant ethanol levels (32). Thus, ethanol inhibition of ADH-catalyzed
AA09731 (to G. D.). The costs of publication of this article were defrayed retinol oxidation may be of concern medically as it could result
in part by the payment of page charges. This article must therefore be in reduced RA synthesis leading to an inhibition of retinoid
hereby marked “advertisement” in accordance with 18 U.S.C. Section signaling or reduced clearance of retinol leading to toxicity.
1734 solely to indicate this fact.
‡ To whom correspondence should be addressed: Gene Regulation
Adverse interactions occur when vitamin A and ethanol are
Program, Burnham Inst., 10901 North Torrey Pines Rd., La Jolla, administered simultaneously. This is particularly noticeable in
CA 92037. Tel.: 858-646-3138; Fax: 858-646-3195; E-mail: duester@ alcoholics who were administered retinol supplements to coun-
burnham.org. ter vitamin A deficiency where it was found that retinol/etha-
1
The abbreviations used are: RA, all-trans-retinoic acid; ADH, alco-
hol dehydrogenase; Adh1, mouse class I ADH gene; ALDH, aldehyde
nol drug interactions occurred that increased hepatotoxicity
dehydrogenase; HPLC, high pressure liquid chromatography; AUC, and carcinogenicity (33). The mechanism of such interactions is
area under curve, WT, wild-type. not well understood but may relate to the fact that ADHs can