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Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University, Ames, IA 50011
3To whom correspondence should be addressed.
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • ß-carotene • retinoids • ß-apocarotenals • rats • central cleavage
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). The major dietary
source of vitamin A in humans consuming primarily vegetarian diets is
provitamin A carotenoids, of which ß-carotene is the major
component.
In mammalian tissues in vitro, provitamin A carotenoids are converted
mainly into vitamin A by central oxidative cleavage, which is catalyzed
by the enzyme carotenoid 15,15'-dioxygenase (EC 1.13.11.21)
(Devery and Milborrow 1994
, Duszka et al. 1996
, Goodman and Huang 1965
, Lakshman et al. 1989
, Lakshman and Okoh 1993
,
Lakshmanan et al. 1972
;1> Nagao et al. 1996
, Olson and Hayaishi 1965
, Olson 1999
, van Vliet et al. 1996
). A minor pathway in
healthy mammals in vivo and in vitro is stepwise oxidative cleavage
from one end of the polyene chain, presumably via a sequence of
ß-apocarotenals, to yield retinal (Ganguly and Sastry 1985
, Gessler et al. 1998
, Glover 1960
, ;2>Sharma et al. 1977
, Tang et al. 1991
, Wang et al. 1991
, Wang and Krinsky 1998
) These pathways are depicted in Figure 1
. The polyene chain of the carotenoid might also be cleaved randomly,
probably by nonspecific lipoxygenases and chemical oxidants. In
oxidative stress, central cleavage tends to be depressed and other
oxidative transformations of carotenoids tend to be enhanced
(Gomboeva et al. 1998
, Yeum et al. 1995
).
|
,
Mattson et al. 1947
, West and Castenmiller 1998
), we decided to determine the extent to which retinal,
ß-apocarotenals and their metabolites, as well as other products,
arise as a result of administering ß-carotene to both vitamin
A-sufficient
(+A)4
and vitamin A–deficient (-A) rats in vivo. Our findings are
summarized in this paper. |
MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Methanol, dichloromethane, 2-propanol, acetonitrile and ethyl acetate were supplied by Fisher Scientific (Fair Lawn, NJ). HPLC-grade solvents were used whenever available.
All-trans ß-carotene in the form of water-soluble beadlets, ß-apo-8'-carotenal, ß-apo-10'-carotenal and ß-apo-12'-carotenal were gifts from Hoffmann-La Roche, (Nutley, NJ). The oral dose of ß-carotene was prepared as follows: ß-carotene beadlets (1 g, 10% ß-carotene, wt/wt) were ground with water (3 mL). When a clear solution was obtained, peanut oil (3 mL) was added and ground well to obtain a uniform solution. The purity and concentration of the ß-carotene solution were checked by spectrophotometry and by HPLC.
Derivatives.
The ß-apo-carotenals were reduced to the corresponding
ß-apo-carotenols by treatment with NaBH4 (Barua and Ghosh 1972
). ß-Apo-carotenoic acids were prepared by
oxidation with Tollen’s reagent, as described in the conversion of
retinal to retinoic acid (RA) (Barua and Barua 1964
).
5,6-Epoxyretinyl palmitate was prepared by treating retinyl palmitate
with 3-chloroperoxybenzoic acid (Barua 1999
). The
ß-apo-carotenols and ß-apo-carotenoic acids were purified by TLC on
silica gel plates, and then tested for purity by HPLC. The oximes of
ß-apocarotenals were prepared by reaction with hydroxylamine, as
described for the preparation of retinal oximes (Landers 1989
), and tested by HPLC for purity.
Animals.
Weanling female Sprague-Dawley rats were obtained through
University Laboratory Animal Resources. All experiments with animals
were in accord with NIH Guidelines for the Use of Animals and were
approved by the University Committee on the Use of Animals in Research.
The rats were kept in individual cages, and fed either a vitamin
A–deficient diet (Diet No. 904646) (-A) or a vitamin A–sufficient
diet (+A) of the same composition, both supplied by ICN, Cleveland, OH.
Both diets (g/kg) contained sucrose (325), cornstarch (325),
vitamin-free casein (180), brewer’s yeast (80), cottonseed oil
(50), and salt mixture #2 (40). Both diets also contained viosterol
(4400 IU/kg), whereas only the vitamin A–supplemented diet
contained retinyl palmitate (14,000 IU/kg, or 14.7
µmol/kg diet). The vitamin A–supplemented ICN diet
contained only 3.5% of the retinyl palmitate (400,000 IU
or 420 µmol/kg diet) present in the AIN-76A and AIN-93
diets (Reeves 1997
). Although it supports growth, this
ICN diet does not induce vitamin A storage in intestinal tissue and
minimizes that in the liver. The weights of rats were recorded at
regular intervals.
The rats fed the -A diet showed signs of vitamin A deficiency, e.g., a weight plateau, after 5 wk. Blood (0.5 mL) was collected from the tail vein of each rat before administering the ß-carotene.;3> Rats from each group (n = 3) were killed at zero time to obtain baseline values. Then, each rat (+A and -A) was given a single oral dose of ß-carotene (5.6 µmol or 3 mg) in 0.18 mL peanut oil. The -A and +A rats (n = 3/group) were killed under ether anesthesia 3 h after the dose. To maximize the formation of ß-apocarotenals, one -A rat was killed 1 h after dosing. Blood, collected from the heart, was allowed to clot, and serum was obtained by centrifugation at 1200 x g for 15 min.;4> The stomach, small intestine and liver were removed and weighed. Serum and tissues were kept frozen at -20°C.
Serum.
Retinoids and carotenoids in serum were extracted under yellow light at
4°C by a slight modification of a published procedure (Barua et al. 1998
). In brief, serum (500 µL) was
mixed with ethanol (1 mL), dilute acetic acid (3.3 mol/L, 0.1 mL),
retinyl acetate in ethanol (internal standard, 7
µmol/L, 20–100 µL) that contained
BHT (46 µmol/L), ethyl acetate (1 mL) and hexane (1
mL). The mixture was vortexed (30 s) and then centrifuged (1200 x g) for 1 min. The supernatant solution was removed, and
the pellet was extracted with hexane (1 mL). The pooled extracts were
vortexed with water (0.5 mL) and then centrifuged, as indicated above.
The organic extract was evaporated to dryness under a slow stream of
argon. The residue was dissolved in a mixture of
2-propanol/dichloromethane (2:1, v/v; 100 µL). The
recovery of the internal standard, retinyl acetate, was 88–95%. All
reported serum values were correspondingly corrected. The efficiency of
extraction of ß-apo-8'-carotenal was similar to retinyl acetate under
the same conditions.
Liver, small intestine with its contents and stomach with its contents.
The extraction procedure was a slight modification of a published
procedure (Barua et al. 1998
). The tissues were first
chopped and minced. Liver (0.2–0.5 g) or 1 g small intestine or
stomach (including contents) was placed in a mortar. The tissue was
ground to a powder with anhydrous sodium sulfate. After the addition of
2 volumes (v/wt) of 2-propanol/dichloromethane (1:1), the mixture was
ground further with a pestle and then allowed to stand for 2–3 min.
The extract was filtered, and the residue was extracted with
dichloromethane 3–4 times, as described. The pooled extract, after
being filtered, was evaporated to dryness in a rotary evaporator, and
the residue was dissolved in 2-propanol/dichloromethane (1:1, 0.5 mL).
An aliquot (50–100 µL) was analyzed by HPLC. The
recovery of the internal standard, retinyl acetate, was 88–95%. All
reported tissue values were correspondingly corrected. The recovery of
ß-apo-8'-carotenal under the same conditions was similar to retinyl
acetate.
Reverse-phase gradient HPLC.
For reverse-phase gradient HPLC (Barua et al. 1998
),
Waters Associates (Milford, MA) pumps (model 510), an autosampler (WISP
model 717 Plus), a pump control module, a photodiode array detector
(model 996) and the Millenium 2010 chromatography manager were used. A
Rainin (Woburn, MA) Microsorb-MV 3 µm
C18 (3.6 x 100 mm) column was used. A 15-min linear
gradient of methanol/water (7:3, v/v containing 10 mmol/L ammonium
acetate) to methanol/dichloromethane (4:1, v/v) or to
acetonitrile/dichloromethane/methanol (95:10:5, v/v/v) at a flow rate
of 0.6 mL/min was followed by isocratic elution with the latter solvent
mixture for another 30 min. The gradient was then reversed to initial
conditions in 5 min. Thereafter, the column was equilibrated with the
initial solvent for 10 min before the next injection was made.
The limit of detection for retinol and retinyl esters by HPLC was 1.8 pmol and for RA and ß-carotene was 3.3 pmol when an injected aliquot of 100 µL was used.
Statistical analysis.
Means were compared using Student’s t test
(Snedecor and Cochran 1989
).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Before dosing, the serum of -A rats had only a trace of retinol,
whereas the serum of +A rats had normal retinol levels (Table 1
). After the dose of ß-carotene, the retinol level in -A rats
increased significantly (P < 0.01) at 3 h,
whereas that in the serum of +A rats rose only slightly (P
< 0.10) (Table 1)
. Retinyl esters reached much higher
concentrations (P < 0.001) at 3 h in the serum of
-A rats than of +A rats. RA also increased more (P < 0.01) at 3 h in the serums of -A rats than in that of +A rats
(Table 1)
. Serum ß-carotene concentrations rose similarly in -A and
+A rats. No other metabolites of ß-carotene, such as the
ß-apocarotenals, were detected in any serum sample of either -A or
+A rats.
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Stomach. In the stomach, including its contents, in both -A and +A rats, ß-carotene rose from undetectable amounts at zero time to 13.5 ± 0.53 nmol/g in -A rats and to 7.2 ± 0.65 nmol/g in +A rats at 3 h.
Two other carotenoids were present in stomach extract at 3 h at
~10% of the concentration of ß-carotene. One of these compounds
was identified as 5,6-epoxy-ß-carotene on the basis of its coelution
with and spectral properties (
max 475, 445 nm)
similar to authentic 5,6-epoxy-ß-carotene (Barua 1999
). The 5,6-epoxy group of the carotenoid was further
characterized by a hypsochromic shift in spectra on treatment with 0.1
mol/L HCl, indicative of the isomerization of the 5,6-epoxy group to a
5,8-furanoid group (max 455, 425 nm)
(Barua 1999
). The 5,8-furanoid form of
epoxy-ß-carotene was not found in the stomach contents. The other
carotenoid resembled a monohydroxy-ß-carotene. Its spectrum was
identical to that of ß-carotene, and its retention time was the same
as that of ß-cryptoxanthin. Retinoids were not detected in the
stomach and its contents.
Small intestine.
In the small intestine, including its contents, ß-carotene rose from
nondetectable amounts at zero time to relatively high amounts at 3 h (Table 2
). Retinoids also increased markedly. Although the overall amounts of
retinol plus its esters that were present 3 h after dosing were
not different in -A and +A rats, the amount of RA present in -A rats
at 3 h was much higher than that found in +A rats (P
< 0.001). A typical chromatogram, obtained at 330 nm for
retinoids and 445 nm for carotenoids, of the small intestinal extract
of -A rats 3 h after the dose of ß-carotene is shown in
Figure 2A
and
B
. The spectra of RA, retinol, retinyl palmitate and ß-carotene, which
were the major peaks in these chromatograms, are shown in Figure 2C
. The unmarked peak eluting at about 24 min in Figure 2A
was tentatively identified as 5,6-epoxyretinyl palmitate
by its chromatographic behavior and max (325,
313, 295 nm). The peaks eluting near 30 min were retinyl esters
(max = 326 nm) of unidentified fatty acid
composition. Because of the large amount of ß-carotene in the
analyzed aliquot (Fig. 2B
), however, considerable absorption
in this elution region was also noted at 330 nm (Fig. 2A
). A
small amount of retinyl ester, probably retinyl stearate, was also
present in this peak at 330 nm (Fig. 2A
). Only trace amounts
of other products were present.
|
|
. In -A and +A rats, at 3 h, retinol and retinyl esters increased
as expected from baseline values; the increase was significant
(P < 0.001) for -A rats but not for +A rats because
of their endogenous reserves. Furthermore, the liver concentrations of
ß-carotene, RA and retinal (0.88 ± 0.50 vs. <0.1 ± 0.1
nmol/g) were higher (P < 0.05) at 3 h in +A than
in -A rats.
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) of intestinal extracts, which
included the lumen contents, several tiny peaks that absorbed at 445 nm
eluted between retinol (20 min) and epoxy-ß-carotene (30 min). In
preliminary studies, these peaks were slightly more prominent at 1 h than at 3 h. To examine these compounds more fully, a fivefold
(5 g) greater amount of the intestine and its contents from a -A rat
was extracted at 1 h after dosing and a fourfold larger aliquot of
the final extract was chromatographed. As shown in Figure 3A
, thirteen peaks appeared in this region (20–28 min); seven of these
have been tentatively identified, namely, retinal, four
ß-apocarotenals (8', 10', 12' and 14'), 5,6 epoxy-ß-carotene, and a
hydroxycarotenoid. The absorption maxima and E1 cm1%
values of the ß-apocarotenoids are summarized in Table 4
, and the spectra of six of the isolated ß-carotene metabolites are
shown in Figure 3B
. Each of the ß-apocarotenals isolated
from the intestinal preparation was reduced to its alcohol and
converted to its oxime. As shown in Table 4
, the observed absorption
maxima of these derivatives agreed well with literature values,
particularly in view of the fact that different solvents were used in
these determinations. The observed absorption maxima for the
ß-apo-carotenoic acids (8', 10', 12') in Table 4
, however, were
derived from chemically oxidized reference compounds, not from
ß-carotene metabolites.
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), or ß-apocarotenoic acids were
detected in the intestinal extract of +A or -A rats at 3 h. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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,
Tang et al. 1991
). No retinoids were detected in the
stomach and its contents.
Because the small intestine is a major site of the conversion of
ß-carotene to vitamin A in vivo (Glover et al. 1948
,
Mattson et al. 1947
, Parker et al. 1994
),
this study focused on the isolation and characterization of products of
ß-carotene in this tissue and its contents. Retinol and retinyl
esters were major products at 3 h, together with smaller amounts
of RA (Table 2)
. The net increase of retinoids (12.7 ± 4.8
nmol/g) in the intestine of -A rats at 3 h was somewhat higher
than in +A rats (9.15 ± 2.9 nmol/g), in keeping with the
observation that the activity of the intestinal central cleavage enzyme
is increased in vitamin A deficiency (van Vliet et al. 1996
).
Retinal and several ß-apo-carotenals were also detected at 3 h
as very minor metabolites in the extracts of small intestines and their
contents of -A rats, but not of +A rats. By use of a sensitive
photodiode array detector during HPLC and a concentrated extract of the
intestine of a -A rat at 1 h, these products were characterized
by their spectra, by their retention time on HPLC, and by the formation
and spectral analysis of two different chemical derivatives. The total
amount of the ß-apocarotenals present at 1 h was ~0.30 nmol/g,
or <5% of the total retinoids present at the same time. Furthermore,
no ß-apocarotenoic acids or ß-apocarotenyl esters, which are major
metabolites of the ß-apocarotenals (Zeng et al. 1992
),
were detected. In this regard, ß-apo-8'-carotenal is converted very
slowly, if at all, to retinal in intestinal homogenates in vitro
(Nagao et al. 1996
).
In addition to the more common ß-apocarotenals (8', 10', 12', 14'),
we identified a HPLC peak (~0.05 nmol/g) with a spectrum,
chromatographic behavior and derivatives similar to those of
carotenoids containing a 6' carbonyl group, e.g., ß-apo-6'-carotenal
(Isler et al. 1959
), citranaxanthin (Yokoyama and White 1965
) and semi-ß-carotenone (Yokoyama and White 1968
). We favor semi-ß-carotenone as the primary product
because its formation by a dioxygenase is analogous to that of all
other carotenoid cleavage products. Semi-ß-carotenone, although
formed biologically in citrus (Yokayama and White 1968
),
has not been suggested previously as a possible product of ß-carotene
metabolism in mammals in vivo. Further study is clearly necessary,
however, to elucidate the structure of this compound.
The extent to which these ß-apocarotenals arise by chemical oxidation in the lumen of the intestine or by enzymatic cleavage in the mucosa is unclear. Because the ß-apo-carotenals were not identified in +A rats nor in tissues of -A rats other than the intestine, ß-apo-carotenals clearly were not formed as artifacts of the isolation and extraction procedures.
The serum of -A rats expectedly showed an increase in all retinoids
and ß-carotene 3 h after dosing, whereas that of +A rats showed
lesser effects. Of particular note is that serum retinol in -A rats
peaked at 3 h at a concentration almost twice that in +A rats.
Furthermore, the serum RA concentration at 3 h was much higher in
-A than in +A rats, in keeping with our observation that retinoyl
ß-glucuronide is also converted more rapidly to RA in -A than in +A
rats (Barua et al. 1998
, Kaul and Olson 1998
).
All retinoids in the livers of -A rats increased markedly at 3 h
after dosing with ß-carotene. Although the liver concentrations of
retinoids were much higher initially in +A rats, the total mean
increment of stored retinoids at 3 h in the livers of +A rats
(35.5 nmol/g) was higher than that of -A rats (28.6 nmol/g). Thus, the
rate of conversion of ß-carotene to vitamin A in vivo may be less
affected by vitamin A status than previously assumed on the basis of
studies with intestinal preparations alone (van Vliet et al. 1996
).
The retinal formed from ß-carotene in the intestine is oxidized to RA
to a greater extent in -A than in +A rats (Table 2)
. Probably as a
result, serum RA is also significantly greater in -A rats (Table 1)
.
The lower concentrations of ß-carotene, RA and retinal in the liver
of -A rats, therefore, may reflect a more rapid conversion of
ß-carotene to retinal, a more rapid oxidation of retinal to RA and a
more rapid release of RA from the liver into the plasma.
In essence, we have confirmed that ß-apocarotenals are formed as
products of ß-carotene oxidation in vivo (Ganguly and Sastry 1985
, Glover 1960
, Sharma et al. 1977
, Wang et al. 1991
). The ß-apocarotenoids
were detected only in intestinal preparations of vitamin A–deficient
rats, however, and were present in that tissue in amounts <5% of the
amounts of retinoids formed there during the same period. These
findings, which agree with those of in vitro studies, support the view
that the central cleavage of ß-carotene is the predominant pathway
for vitamin A formation in healthy mammals.
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FOOTNOTES |
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2 Supported in part by National Institutes of Health-DK39733, U.S. Department of Agriculture-NRICGP 97–37200-4290 and U.S. Department of Agriculture/CDFIN 96–34115-2835. Journal Paper No. J-18838;8> of the Iowa Agriculture and Home Economics Experiment Station, Ames, IA, Project No. 3335, and supported by Hatch Act and State of Iowa Funds.
4 Abbreviations used: +A, vitamin A-sufficient; -A, vitamin A-deficient; RA, retinoic acid.
Manuscript received December 13, 1999. Initial review completed January 19, 2000. Revision accepted April 6, 2000.
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