Beta-carotene
Martin
R Prince
and
ABSTRACT
skin was evaluated
of 3-carotene
accumulation
Joan
The accumulation
off3-carotene
in serum
in human
volunteers.
A single S I -mg
given
in the
as high
absence
of dietary
the
same
daily in three
concentration
total
dose
in no
divided
three
for serum
ofskin
color
in skin was
fat and is enhanced
long time constant
accumulation.
by administering
with meals but there is a
for serum
(10 d) and tissue
(several
weeks)
Am J C/in Nutr l993;57:175-8l.
KEY
WORDS
Atherosclerosis,
nutrition,
lipid,
accumulation.
requires
dietary
carotenoids,
lipoprotein,
laser
is in the
angio-
family
that
occur
naturally
in plants
and are consumed
by humans
in the
form of green and yellow
vegetables.
Although
the function
of
carotenoids
in plants
is not completely
understood,
their lipoand
ability
to quench
reactive
chemical
species
suggest
that they may be important
for protecting
plant
membranes
during
photosynthesis
(1). In humans,
carotenoids
and especially
/3-carotene
are an important
source
of vitamin
A and are also
postulated
may
to protect
induce
evidence
(5).
plaque
cancer
that
human
and
cells
carotenoids
can
induce
Their
ability
to accumulate
makes
selective
removal
radiation
tuned
to the carotenoid
dition,
a carotenoid
shown
to play
organogenesis
Despite
accumulation
from
atherosclerosis
metabolite,
a fundamental
the
reactive
(2-4).
There
species
is also
cell-mediated
that
absorption
role
peak
acid,
in cell
(6-9).
recently
In adhas been
differentiation
dose/regimen
of 13-carotene
for each of the
is not known.
J C/in
Nuir
1993:57:175-81.
potential
clinical
is known.
A single
in serum
/3-carotene
Printed
in USA.
serum
dose
that
variable
from
Although
absorption
several
investigators
in subjects
on high-fat
dietary
which
rather
it difficult
to
of daily
low
at these low doses
over a period
of
dose,
180
than
intervals
ofthese
than
mg/d,
the lowso the
studies
specifically
to know
exactly
meahow
the
changed.
reported
increased
fl-carotene
diets, it is not known
whether
fat is essential
for fl-carotene
absorption.
fl-carotene
absorption
can be enhanced
with
the
entire
day’s
is no information
in tissue,
which
The
d
fraction
individual
studies
intermediate
carotenoids
making
of 4-12
is a small
data
fat consumption
of which
have
been
peutic
potential
than
fl-carotene,
of accumulag serum
of other
hypothesized
to have
are scarce
(24,
to
is also
about
the rate
may significantly
on accumulation
some
The extent
by administering
carotenoids,
greater
25).
thera-
Thus,
it is
difficult
to know what dose, regimen,
and carotenoid
to administer ifthe goal is to deliver
the maximum
amount
of carotenoid
to serum
and tissue in the shortest
Our interest
relates to preferential
in lipid-rich
atherosclerotic
plaques.
to plaque,
making
it easier to identify
at surgery
selective
removal
of atherosclerotic
plaque
with
tuned
to a carotenoid
absorption
peak. For this
application
the highest
it is necessary
to know how long
tissue
carotenoid
concentrations.
it takes to
It is implaque
practical,
however,
to serially
humans,
so instead
we monitored
in
period
of time.
accumulation
of fl-carotene
Dietary
carotenoids
confer
sample
serum
and in a more
accessible
ofthis
study was to determine
atherosclerotic
accumulation
lipophilic
in
of fl-carotene
tissue,
I) the importance
skin. The
of dietary
and
(10).
this interest
in f3-carotene,
its absorption
and
are not completely
understood.
Beta-carotene
Some
kinetic
information
otene
results
in an increase
Am
total
fl-carotene,
concentrations
goal
tissue
was
approved
for medical
use as an orphan
drug to treat a rare photosensitizing
skin disorder,
erythropoietic
protoporphyria
(1 1,
12). Basic
pharmacokinetics
studies
were not required
so the
optimal
cations
a period
indicate
that
is reached
at an
/3-carotene
clinical
achieve
lysis
in lipid-rich
atherosclerotic
of plaque
possible
with laser
retinoic
is highly
1). A study
d (1 5-2
over
absorbed
pharmacokinetic
5-20
a yellow
color
and permitting
laser radiation
recent
tumor
is cleared
mg /3-carotene/d)
serum
concentration
unknown.
There
lation offi-carotene
of pigments
and
early
it in association
pharmacokinetics
carotenoid
dose
Several
accumulation.
Beta-carotene
and
of /3-carotene
doses (1 5-60
a steady-state
suring
Introduction
philicity
ingested
individual.
monitored
2 wk
plasty,
ingestion
amount
does not show faster serum
carotene
accumulation
dose studies
but the blood
was drawn
at 2-wk
kinetics
were not clearly
defined
(22, 23). Many
delayed
by up to
These
data indicate
that
with serum
absorption
once
oral
14). The
of the
doses
times
administered
regimens
had the same
time constant
9-10
d. Remittance
measurements
that the accumulation
of /3-carotene
compared
fl-carotene
50 h after
( 1 3,
appliof f3-carpeaks
6-
© 1993 American
Society
I From
the Department
of Radiology
and the Wellman
Laboratory,
Massachusetts
General Hospital,
Harvard
Medical School, Boston, MA.
2 Supported
in part by NIH grants HL44274
and HL46384,
an RSNA
Research
Resident Award, and the SDIO MFEL program under contract
N000 14-86-K-00l
6.
3 Address
reprint requests to MR Prince, Department
of Radiology,
Massachusetts
General
Hospital,
Fruit Street, Boston, MA 02 1 14.
Received
May 5, 1992.
Accepted
for publication
September
15, 1992.
for Clinical
Nutrition
175
Downloaded from ajcn.nutrition.org by guest on June 8, 2015
a day: both
accumulation:
demonstrated
with
fat resulted
and
dose
The same dose admin/3-carotene
2.5-fold
at 40
administering
a-carotene
raised the serum /3-carotene
compared
and skin13
K Frisoli
detectable
change
in serum
/3-carotene.
istered
with 200 g fat increased
serum
h. Similarly,
with meals
in serum
PRINCE
176
fat for fl-carotene
fl-carotene
the entire
day’s
are
ofaccumulation
study
on
in the
multiple
the
rate
magnitude
the
3) the rate
stratum
and
Food
mg/d,
corneum,
were
magnitude
of
the
effects
12,
fat. Additional
1 8, 24,
In the
Adrate
tissue.
to
FRISOLI
no dietary
over
and Drug
and 4) the
given
the confounding
of
dose
a lipophilic
regimens
to eliminate
and
by spreading
the maximum
dose of 300
carotene
set ofindividuals
to-human
affected
fat consumption,
fl-carotene
absorption
ministration-recommended
this
2) how
absorption,
absorption
AND
with
48,
regimen
with
two-thirds
168
fat
pint
samples
were
drawn
h post-fl-carotene
fl-carotene
ice cream
(5 1 mg)
containing
at 3, 6, 9,
administration.
was
administered
200 g fat (vanilla
swiss
almond,
Haagen-Daz
Co Inc. Teaneck,
NJ) and serum
samples
were drawn
at 1, 2, 3, 4, 6, 9, 12, 18, 24, 36, 48, 72, 168, 320,
In
and
same
of human-
640
h post-fl-carotene.
-70#{176}Cfor later
All
serum
samples
were
stored
at
analysis.
variability.
Multiple-dose
Subjects
and methods
Subjects
experiments
Once the importance
was established,
a series
of dietary
fat for fl-carotene
of multiple-dose
regimens
taken
absorption
to determine
spreading
Five healthy
volunteers,
two females
(subjects
4 and
informed-consent.
The
three males (subjects
1 , 2, and
5), took regimens
offi-carotene
study
protocol
was
Committee
in Table
on Human
1 . Throughout
Massachusetts
General
Hospital
Their characteristics
are shown
periments
the subjects
maintained
with a consistent
amount
ofdietary
3) and
under
approved
their normal
fat.
by
the
dietary
4)
pattern
were
diospectrum,
mg soybean
performed
Walpole,
MA)
oil, 6 mg lecithin,
with
fl-carotene
capsules
units
oxidative
random
A.
The
decomposition.
sampling
ofcapsules
measured
periodically
solution.
The
capsules
fl-carotene
was
fl-carotene
content
and
stable over the course
and 3% 1 5-cis-fl-carotene.
purity
eluding
dissolving
ofa dilute
ofthis
of the study
single
with
97%
mg
three
times
a day
with
meals
by
by in-
(300 mg/d).
with breakfast
(subjects
1-4), and
(subjects
1-5).
[Data
was a period
of
2 mo without
fibetween
each regimen.
Fasting
blood
stored
at -70#{176}C on day 0 (before
every
Monday,
exact dates depen-
dent on the subject’s
schedule.
Compliance
was monitored
by
asking
subjects
at the time ofeach
blood
collection
ifany
doses
had been missed.
The time of onset
of known
side effects,
in-
during
the study by extracting
fl-carotene
from the capsules,
it in hexanes,
and measuring
the absorption
spectrum
fat and
34
starting
fl-carotene)
and then
approximately
Wednesday,
and Friday
for 3-4 wk with the
soybean
oil and lecithin
fl-carotene
content
of a
The
was
are affected
dietary
dose to the maximum
recommended
were as follows:
1) 5 1 mg once a day
for each subject
and there
carotene
supplementation
was drawn
and the serum
(Car-
containing
1 7 mg fl-carotene,
180
and 35 mg wax packaged
in gelatin
of vitamin
kinetics
day’s
from this regimen
have been reported
previously
in a short communication
(26).J
The order in which
the regimens
were undertaken
was varied
capsules.
This preparation
is commonly
sold in grocery,
pharmacy,
and health-food
stores
under
various
labels as 25 000 international
102
and
an entire
orange
stool
and
yellow
skin
subjects’
diets were not controlled,
a consistent
dietary
pattern
was
lot of
collected
trans-
timated
and
each
from
subject’s
a dietary
color,
was noted.
the importance
stressed
each
average
dietary
Although
of maintaining
time serum
was
fat content
was
es-
record.
A nalysis of serum
Single-dose
evperiinents
To evaluate
the
sorption,
subjects
and without
200
The
importance
of dietary
fat for carotenoid
2-4 took 5 1 mg fl-carotene
g fat. In the no-fat
regimen,
frozen
serum
and 0.5 mL serum
acetate
(an internal
(3 capsules)
with
subjects
fasted for
a minimum
of 12 h before
the study.
Baseline
serum
were drawn
before
and during
fasting.
Beta-carotene
was then administered
orally followed
by an additional
TABLE
ab-
for 20 5 the
with hexanes.
samples
(5 1 mg)
6 h with
high-pressure
previously
was
allowed
ethanol-serum
The extracted
liquid
(27).
to thaw
at room
was mixed
with a solution
standard)
in 0.5 mL ethanol.
mixture
lipids
was extracted
three
were further
separated
chromatography
(HPLC)
consisted
of a C-l 8, 5-sm,
This
temperature
of 1 zg retinyl
After vortexing
method
times
by a
described
reverse-phase
1
Characteristics
of subjects0
Seru m lipids
Subject
Sex
Age
LDL
HDL
Di etary
Trig
Chol
Height
gIL
Weight
B
L
fat
D
Total
NA
m
kg
I
M
36
1.75
0.60
0.78
2.51
1.76
70
NA
NA
2
M
31
1.27
0.46
0.65
1.86
1.63
57
1
12
59
72
3
M
30
1.19
0.47
1.02
1.86
1.70
73
8
56
73
137
4
F
31
0.77
0.92
0.56
1.80
1.60
48
5
19
49
73
5
F
31
0.96
0.58
0.57
1.66
1.70
57
12
28
48
88
1,
0
Trig, triglycerides:
t B, breakfast:
Chol,
L. lunch:
cholesterol.
D, dinner:
Total,
daily
total:
NA, not available.
g
NA
Downloaded from ajcn.nutrition.org by guest on June 8, 2015
Experiments
3)
1-5),
over
absorption
was under-
2-5),
2) 1 7 mg three times a day with meals
mg three times a day with meals (subjects
(subjects
Studies.
the cx-
how
fl-carotene
creasing
the
The regimens
Beta-carotene
inhibit
serum
and
72,
BETA-CAROTENE
column
(LC18
Supelco,
Bellefonte,
(acetonitrile-methylene
1 .7 mL/min.
For
(the
at 450
each
nm,
internal
amounts
specimen,
whereas
standard)
lipids
were
resuspended
in 0.5 mL
and
were
other
monitored
at 327
retinol,
from the areas under
periodically
calibrated
each
and
the purity
coefficient
spectively
(28)].
of extracted
The
of the
using
2590,
Extraction
yield
measured
species
the computer
3450,
1835,
Fig 1). When
administered
fl-carotene
in serum
15 10, re-
3-6
was
in serum
calculated
with
Excel(4.0;
Microsoft,
the
values
concentrations
Student’s
at time
on or extrapolated
t test
by
Seattle,
WA).
0 were
com-
to day
multiple-dose
value with
2, A-D.
The
including
(LDL),
high-density
triglycerides,
lipoprotein,
and
cholesterol,
concentrations
fl-carotene
serum
fl-carotene
fitted
accumulation
were
measured
time
constant,
r,
to a first-order
model
for
given
by
-
once
a day.
and
to be 100%.
concentrations
A is the
maximum
The data show,
a multicompartment
baseline
increase
however,
serum
in serum
(1)
fl-carotene
fl-carotene
and
r is
that the kinetics
are more cornmodel
would
be required
to fit the
no
(see
resulting
increase
2.8%
in serum
peaked
of the
in a 2.5-fold
fl-carotene
at 36-48
h.
The
regimen,
the serum
fl-carotene
reached
a time constant
of 9- 10 d as shown
in
orange
None
of the
compliance
observed
serum
on the regimen
reported
ofthe
at -3-5
d and
the
skin
10 d in all subjects
on the regimen
of
times a day but not on the regimen
fl-carotene
of S 1 mg
in earlier
same
total
subjects
found
these
in the five subjects
and
once
studies
amount
total carotenoid
a day are com-
on similar
given
side
appeared
regimens
in one
dose
given in three divided
doses with
that three times greater
absorption
(with
meals
was
obtained
when the fl-carotene
was administered
(P < 0.001) (see Tables 2 and 3). As the fl-carotene
over three meals
dose increased
from
with
1 7 to 34 to
102
mg
three
times
average
steady-state
serum
fl-carotene
3.4 to 7. 1 mg/L but the time constant
tration
+
exp(-t/r))
with
in the serum
g fat, however,
and
turned
breakfast)
vs the amount
(Fig 2, A and B) reveals
at multiple
200
absorbed,
The
at
three
bothersome
affected
A (1
=
were
low-density
taken
stool
parable
with those
(14, 16, 19, 29).
20 of each
with
was
administration
began to turn yellow
17, 34, and 102 mg
effects
of fasting
experiments
On each
a steady-state
Fig
a period
accumulation
fl-carotene.
h after
Multiple-dose
after
no detectable
administered
Comparison
serum
data
ret-
administered
fat showed
of 5 1 mg
measured
lipids,
serum
time.
plex;
Beta-carotene
began
as the fraction
by the hospital
chemistry
laboratory
on serum
times during
the course
of the study.
To determine
an approximate
serum-rise
where
and
experiments
increase
acetate
lycopene,
was determined
regimens
those
lipoprotein
the
absolute
each chromatogram
peak.
with known
amounts
of
of changes
program
multiple-dose
Serum
The
retinyl
acetate.
significance
the
acetate
standards
was assessed
by comparing
of each compound
with its known
cx-
statistical
pared with
regimen.
nm.
and
177
(Fig
2 and
obtained
Table
by each
3). Figure
subject
a day
concentration
(10 d) was not
3 shows
meals,
the serum
as a function
the
rose from
significantly
concen-
of dose
and
the
average
ofall
subjects
at day 20 on each regimen.
The baseline
value was lowest for 5 1 mg once a day for two reasons.
For three
of the subjects,
this
subjects,
the interval
and
the
previous
was their
first regimen;
for the other
two
between
the regimen
of 5 1 mg once a day
regimen
was
longer
than
the
other
intervals.
precisely.
Remittance
spectroscopy
0.7
To evaluate
lipophilic
the
rate
stratum
obtained
mg three
ments
at which
corneum,
fl-carotene
remittance
spectra
on three ofthe
subjects
during
times a day). A spectrophotometer
Inc.
Fullerton,
CA)
fitted
that included
a port
measure
remittance
to exclude
from 600
Data
were
from
palm
(thenar
obtained
with
their
a 1 5-cm
for
each
region
time
in the
of palms
‘-
were
0.6
final regimen
(34
(Beckman
Instruintegrating
specular
reflectance
to 300 nm in 1-nm
a 1-cm2
eminence)
accumulates
was used
increments.
of skin
point.
on
The
0.5
sphere
to
the
right
device
was
.
0.4
0.3
also calibrated
at each time point by obtaining
a spectrum
with
the sample
beam
blocked
(zero
remittance)
and a spectrum
with a 100% remitting
plate freshly
coated
with barium
sulfate
(white
reflectance
coating
no. 6080,
Eastman
Kodak
Co.
0.2
Rochester,
0.0
NY).
-log(remittance)
from later
fl-carotene.
not
Absorbance
for each
was
day.
spectra
to see changes
Although
the absolute
be determined
from
by
measuring
the
day
spectra
individual
the relative
fl-carotene
0 scan
by
calculating
was
subtracted
0
in the absorption
because
of
amount
of fl-carotene
could
remittance
scattering
coefficient
for each
it was possible
to determine
in skin
The
determined
peak
because
the
skin
subject
was not known,
amount
of fl-carotene
heights
for
each
0.1
scan.
Time
(hours)
FIG 1 . Serum
response
to a single dose
tative subject with and without dietary fat.
during fasting. [J there is no appreciable
The same dose administered
with 200 g fat
in fl-carotene
peaking
200
100
at 40 h.
of fl-carotene
for a represenAfter 5 1 mg 3-carotene
taken
change in serum fl-carotene.
10] shows a fourfold increase
Downloaded from ajcn.nutrition.org by guest on June 8, 2015
On
retinyl
of the fl-carotene,
[Em
retinyl
Single-dose
of the
was mon-
A) and
SKIN
at
evaporated
carotenoids
(vitamin
lycopene,
inol, and retinyl
acetate
the absorption
spectrum
AND
Results
solvent
10) flowing
the hexanes
were determined
The HPLC
was
compound
70:20:
SERUM
dietary
retinol
of fl-carotene,
tinction
an isocratic
chloride-methanol,
under
nitrogen
and residual
mobile
phase of the column.
The absorption
offl-carotene
itored
PA) with
IN
1 78
PRINCE
AND
FRISOLI
2.0
aD
%%
00
!1.5
C’)
(I)
0.
.
1.0
a)
J
0
f..
.4-,
0
c_)
0
0.5
a)
U)
a)
U)
0.0
Time
(Days)
Time
(days)
8
-3
00
00
6
In
In
4
a)
a)
4-,
4.)
0
0
I.,
$4
0
a-carotene
Retinol
(eve.)
Lycopene
(eve.)
-
0
-
.-..
-
2
E
Yellow
Skin
‘4
$4
a)
a)
U)
Co
0
0
10
20
Time
30
0
40
10
20
(days)
Time
30
40
(Days)
FIG 2. Serum carotenoid
concentrations
for human
subjects
1-5 on oral fl-carotene.
[-]
shows individual
ficarotene
concentrations.
[ . . . ] shows the average lycopene, [--- -] shows average retinol (vitamin A), and [-]
shows
the fit to fl-carotene
data. A: 50 mg once a day, fit: 0.78 [1 - exp(-t/9
d)] + 0.36 mg/L. B: 17 mg three times a day,
fit: 2.93 [ 1 - exp(-t/9
d)] + 0.49 mg/L. C: 34 mg three times a day, fit: 3.59 [I - exp(-t/l0
d)} + 0.53 mg/L.
D: 102
mg three times a day, fit: 6.38 [1 - exp(-t/lO
d)J + 0.68 mg/L.
TABLE
Serum
2
carotenoid
and vitamin
Dose
A response
J-carotene
to 20 d on oral fl-carotene0
Carotenoids
Vitamin
(0
=
Lycopene
(n = 5)
0.33
± 0.18
1.76
± 0.36
0.37
± 0.07
0.32
± 0.12
2.21
± 0.25
0.31
± 0.03
0.21
± 0.06
4.67
± 0.32*
0.35
± 0.09
0.28
± 0.12
a day
1.1 ± 0.3
4)
I 7 three times a day
(n = 5)
34 three times a day
(n = 4)
102 three times a day
(n = 5)
3.7 ± 1Sf
4.88
± l.60t
0.43
± 0.06
0.26
± 0.1 It
6.1
7.39
± 0.911
0.39
± 0.05
0.25
± 0.l3t
SD.
calculated
S
#{149}
(P
trations
of one
the regimens
no significant
0.05).
<
Figure
of the
of three
change
4 shows
other
the average
carotenoids,
serum
lycopene,
concenfor each
of
times a day. Retinol
(vitamin
A) showed
on any of the regimens.
No significant
ing/L
ng
Baseline
5 1 once
A
decrease
Baseline
3.2
± 0.3
± 1.0*
from
values
unaffected
by a prior
fl-carotene
regimen.
ff1 Significantly
different
from
tP
baseline:
<
0.05.
P
<
0.01,
§P
<
0.001.
TABLE 3
Beta-carotene
regimens
to its original
regimens.
concentration
At the highest
a day, the serum
the baseline
despite
doses,
34 and
concentrations
never
completely
returned
waiting
2 mo
in between
102 mg fl-carotene
of other
carotenoids
three times
began
to
kinetics
for each regimen0
Baseline
Steady-state
Rise
Decay
Dose
fl-carotene
fl-carotene
time
time
mg
mg/L
mg/L
d
d
0.36
1.14
9
15
0.49
3.42
9
15
0.53
4.12
10
15
0.68
7.06
10
15
51 once
aday
(n = 4)
1 7 three times
(n
On subsequent
serum
=
a day
5)
34 three times
(n = 4)
a day
102 three times a day
(n
0
prior
=
5)
Baseline
regimen
based
on serum
is 0.33
mg/L
fl-carotene
for all subjects.
concentrations
unaffected
by a
Downloaded from ajcn.nutrition.org by guest on June 8, 2015
‘0
0
‘0
.
BETA-CAROTENE
IN
SERUM
AND
179
SKIN
7
Serum
00
decay
following
.
34 mg
tid
-3
6
011
.
3
a)
.4-,
0
5
11)
$4
(0
4)
0
‘4
4
Subject
2
.
Subject
4
3
2
I
1-
Subject
A
(0
0
3
I,
a,
Co
2
‘4
4)
S
tid
0
Qd
A
.
0
FIG 5. Decay
0
100
Total
FIG 3. Effects
200
Daily
Dose
a day.
300
with
(mg)
error
bars
and
show
times
(3-carotene
concentrations
standard
a day
error
of the
markedly
and
compared
mean.
Note
significantly
with
the
that
giving
increases
same
dose
serum
given
once
a
show
from
When
oral
fl-carotene
between
or total
though
LDLs
any
of the
carotenoid
fl-carotene
(30).
three
fl-carotene
this data
times
to baseline
concentra-
was collected.
continued
days after
to release
the final
modeled
fl-carotene
oral dose,
with
measured
lipids
concentration
is known
to
be
and
was
transported
the
serum
fl-carotene
decayed
(see Fig 5) with a half-life
of 10 d
with dose. Because
the small bowel
a single
to normal
within
a few days
within
2 mo of discontinuing
fl-carotene
34 mg
exponentially
individual
which
was stopped,
approximately
exponentially
that did not vary appreciably
quately
day.
correlation
stopping
serum
one
three
60
regimen
maximum
fl-carotene
subjects
after
approximately
of 10 d. Symbols
for the three
1
50
(days)
fl-carotene
decays
.
40
and
into the bloodstream
for several
the serum
decay
cannot
be adeexponential.
The
the skin color
fl-carotene.
stool
returned
returned
to normal
serum
identified,
al-
in
by
serum
Tissue
The
accumulation
u/fl-carotene
characteristic
is clearly
evident
mittance
data
three-peaked
in
(see
fl-carotene
absorption
Fig 6). The
spectra
observed
absorption
derived
profile
from
fl-carotene
skin
re-
absorption
maxima
in skin at 475. 490, and S 10 nm are red-shifted
40
nm relative
to those maxima
in hexanes.
Carotenoid
absorption
0.4
spectra
decreases
are
typically
and
stabilizes
red-shifted
as the
the excited
polarity
electronic
of the
states.
There
solvent
may
-3
00
4)
0.3
C)
0
4)
4.)
4.)
0
0
-3
C)
‘4
00
0
‘4
-3
4)
U)
0.2
350
0
5
10
15
20
25
30
400
450
Wavelength
Time
change
in the average
At 34 mg [A] and
102 mg
significant
in the
decrease
concentrations
during three regI 7 mg three times a day [0], there
lycopene
[#{149}]
fl-carotene
average
550
600
(nm)
(Days)
FIG 4. The average serum lycopene
imens offi-carotene.
On the low dose,
is no clear
500
35
serum
concentrations
three
lycopene
for five subjects.
times
a day. there
concentrations.
is a
FIG 6. Change in skin absorbance
for subject 4 after 43 d on 34 mg
three times a day. [-]
shows
the change
in skin absorbance
calculated
from the skin remittance
measurements
and the [- --] is the absorption
spectrum
offl-carotene
in hexanes taken with the same instrument.
Note
the significant
red shift (40 nm) of the fl-carotene
absorption
in skin
compared
with its absorption
spectrum
in hexanes.
Downloaded from ajcn.nutrition.org by guest on June 8, 2015
The
ofdose
the
of serum
fl-carotene
a half-life
tions
on serum fl-carotene
concentrations.
concentrations
obtained by individual
subjects on the three times a day with meals regimen,
and the average
data are represented
by [#{149}].
[---]
show fl-carotene
concentrations
for the
once-a-day
regimen
with the average concentration
indicated
by [0].
show
Serum
,
.
30
Time
1
-
,
.
20
U)
[-]
,
.
10
PRINCE
180
also
be some
ferential
feature
not
red
shift
penetration
at 370 nm
related
to the
wavelength-dependent
It could
a carotenoid
metabolite
The relative
amount
be due
to cis-fl-carotene
was calculated
nm and is plotted
4, the absorbance
closely
followed
serum fl-carotene
in subjects
2 and 3 the increase
concentrations
in skin absorption
by 2
wk relative
to the
accumulation.
reflect
differences
in skin
serum
thickness
one individual
to the
include
variable
rates
that
or possibly
FRISOLI
a
0
C)
.4-)
c0
or an impurity.
of fl-carotene
in skin
the change
in absorption
at 490
of time in Figure
7. In subject
subcutaneous
dif-
depth ofvisible
light in skin. The absorption
(Fig 6) was observed
consistently
in some but
in all subjects.
from
would
AND
0
a
CO
.4-)
.4-)
with no delay:
was delayed
This
can
C)
from
as a function
at 490 nm
vary
delay
C)
‘4
may
00
0
considerably
next.
Other
possible
of uptake
into the
-3
explanations
basal cells and
10
FIG 7. Change
with
time
on
has
regimen
for each
to predict.
promise
of its potential
These
data
on
but
the
optimal
applications
serum
and
has
skin
dose
been
it is taken
confirm
that
fl-carotene
in association
observation
and
is absorbed
in serum
with
a high-fat
further
in the absence
fl-carotene
achieved
reveal
that
ofdietary
by dividing
over three meals as compared
with
significant
(threefold)
enhancement
without
having
to increase
dietary
the
taken
every other
same
total amount
Another
possibility
the daily meal
ported
factors
include
appears
fl-carotene
in this
dose
These
data
fat. Other
previously
refl-carotene
absorption
female,
or lean (3 1) but their impact
that the effect ofdietary
fat observed
demonstrate
that
analyze
bowel
accepts
a bolus
releases
the fl-carotene
a multicompartment
fl-carotene
of lipid within
into the serum
exceeding
50 h. This presumably
the fl-carotene
to be absorbed
packaged
with lipids,
and then
continuous
oral
model
absorption.
a few hours
over a much
The
administration
the
serum
is
small
of eating
but
longer period,
reflects
the time required
into
intestinal
mucosal
released
as chylomicrons.
is observed
several
for
cells,
With
in this
can
linearly
with
administered
were
decreasing
that
at high
elevation
The
pared
spectral
with
are at least
for fl-carotene
Because
testinal
fl-carotene
in other
three
compartments
accumulation
it is unlikely
tract
could
that
accumulate
and
any
with different
perhaps
more.
tissue
fl-carotene
other
than
faster
time
the
than
constants
gastroinit accu-
shift
dose
mg
as
fl-carotene
three
the maximum
accumulation
(Fig 3) and
times
did
at the high-
a day)
increased.
fl-carotene
(12),
which
are likely
before
Serum
increasing
other
carot-
These
competes
may
require
in using
the
peak.
Ifthe
fl-carotene
comparable
with
laser
wavelength
would
emit
laser,
(a gas
findings
with
other
intravenous
ca-
admin-
fluoride
The
laser
skin
compliance
and
have accumulated
not
range.
region,
effects
yellow
angioplasty
with
result
presumably
(C
the
because
helpful
Irene
suggestions.
Kochevar,
loading
lasers
flashlamp-excited
laser),
laser),
been
and
reported
marker
dye
argon
the
ion
argon
previously.
for
evaluating
when and which
lipophilic
amounts
ofpigment.
These
that
show
provitamin
of feedback
that
Tayabba
Hasan,
vitamin
A (fl-carotene)
tissues
results
A toxicity
concentra-
inhibition.
We thank Margo Goetschkes,
Glenn LaMuraglia,
Roxanne
Sylora, Micheline
Mathews-Roth,
Norm
Bendich,
optimal
several
(a solid-state
be a useful
studies
high
plaque
the
post-fl-carotene
all have
determining
significant
from
then
A transition).
-
may
previous
be-
absorption
Fortunately,
(a semiconductor
observed
color
skin,
including
sapphire
angioplasty
carotene
in atherosclerotic
in
laser
selenium
excimer
side
shift
10-nm
as cornimportant
laser
at the
observed
titanium
laser),
emit
absorption
470-5
in tissue
is particularly
to enhance
must
that
spectral
doubled
absorption
solvents
fl-carotene
for selective
in this
other
chosen
be in the
The
of fl-carotene
and
cause
tions,
reported
for
Accumulation
concentrations,
be expected.
( 100
of fi-
applications
protoporphyria
angioplasty
(9),
fl-carotene
fl-carotene
hexanes
to consider
accumulation
in buccal
mucosa
tissues may be different.
Thus,
there
data
(29).
is consistent
carotene
doses
of serum
does
accumulation
by 2 wk compared
istration.
also agree
oftissue
eminence
accumulation
rotenoids
for absorption.
Ifthis
is the case, then only a minimal
additional
increase
in total serum
carotenoids
can be achieved
by increasing
the fl-carotene
dose further.
Higher
and more rapid
with
scale
3 is delayed
therapeutic
on oral
benefit
lation.
time
possible
weeks
not increase
study to accumulate
fl-carotene
with a time constant
ofthe
order
of9-10
d. The remittance
data indicate
that skin accumulation
may be delayed
by up to 2 wk compared
with serum
accumuThis
potential
therapeutic
suggest
the
meals.
with
the
the highest
to require
is
to completely
in serum.
enoids
study.
required
mulates
est dose
of weeks
are
clinical
trials
using 50 mg
day might
be improved
by administering
of fl-carotene
in divided
doses with
is to administer
a once-a-day
regimen
being a nonsmoker,
to be far less than
no
increase
a once-a-day
regimen
enables
of fl-carotene
absorption
fat. This regimen
is counter-
that contains
the most
associated
with increased
thenar
The
serum.
carotene,
including
treating
erythropoietic
tumor
therapy
(5), or enhancing
laser
demand
data
essentially
intuitive
because
pharmaceuticals
with a half-life
not generally
administered
three times a day. The
offl-carotene
to prevent
cancer
and atherosclerosis
2 and
over
a day).
ac-
These
fat. The
times
dif-
fl-carotene
diet.
in their
in skin
three
ofsubjects
with its accumulation
cumulation
demonstrate
important
aspects
of fl-carotene
absorption
and tissue accumulation
that should
influence
its therapeutic
application
and potential.
Beta-carotene
absorption
into the body is known
to increase
when
in the skin
mg
50
(Days)
absorbance
(34
40
and
John
B
Jerry Stringham,
Krinsky,
Adrienne
Parrish
for
many
Downloaded from ajcn.nutrition.org by guest on June 8, 2015
ficult
therapeutic
in 490-nm
fl-carotene
of/I-carotene
Beta-carotene
30
Time
fat.
Discussion
and
20
BETA-CAROTENE
IN
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16.
1 . Krinsky
8.
AND