Plasma tocopherol concentrations in response to supplemental vitamin E

Plasma tocopherol concentrations to supplemental vitamin E13 Nikolay Wanda

V Dimitrov, Chenoweth,

ABSTRACT various doses schedules. or

Cheryl Meyer, Dennis and Winfred Malone

Normal healthy dl-a-tocopherol

of

Administration

1200

IU)

of dl-a-tocopherol

of plasma

a-tocophcrol

12-24

h. Chronic

administration

or

1 320

mg/d

affected diet

by dietary

showed

trations of this similar

fat intake.

significantly

WORDS humans

at

(440,

state

that

Discontinuation with a decline

Individuals

greater

880,

occurred

of the treatof plasma a-

consuming

plasma

was

a high-fat

a-tocopherol

healthy

concen-

Am J C/in

individuals.

Vitamin

a-tocopherol,

E (a-tocophcrol)

E acts in concert cell from

vitamin

E, bioavailability,

has attracted epidemiologists, in free radical

with a number

damaging

oxidative

icals

are

that

radical-scavenging

cells

against

involved

cancer-chemopreventive The protective dependent

on

In addition,

ofreactions

agents

such

(4-6).

experiments

suggest

ki-

agents

use

of basic because Vitamin

to protect

intra-

net effect

E may

utilization

lipids are

copherol-binding

studies

protein

Am J C/in Nutr

199l;S3:723-9.

on

This

and

can

by other

other

factors

be predicted

in question.

of an agent

depends

substantially

investigators by clinical

a thorough

studies but

in rat-liver was

also Printed

cytoplasm demonstrated in USA.

and

sub-

tocoph-

(17-19).

The

ofa

given

studies

study

E will be necessary before in cancer-chemoprevention

trials. The plasma kinetic a great deal of information

the

on plasma

on bioavailability only

Thus,

of mi-

in part,

of the

of the plasma

vitamin

E can intervention

done in the past lack some details

be

contributed that are

of

clinical importance (19-21). For example, the frequency of blood samplings was insufficient and the plasma clearance (to baseline) in single-dose and chronic dosing was not always determined (19-23).

To

obtain

developed

more

information,

a program

the

for testing

National

new

that

used

single

and

experimental

multiple

doses

Cancer

Institute

chemopreventive

agents

intervention trials. In from a phase-I study

of a-tocopherol

under

dif-

conditions.

and methods

Subjects

62 y were

healthy assigned

individuals to the protocol

of the ages of the subjects 21; 41-50

y, 16; 51-60

were

Pregnant

(males

and

for this

study.

24-30

y, 8; and 61-65 study

ifthey

any medication,

women

or those

females) The

y, 15 subjects;

aged

31-40

y, 4. Individuals had

no acute

vitamins, ofreproductive

24-

distribution

y, were

or chronic

or mineral age who

is usually or plasma. for short or

on the tract in plasma

bioavailability

explain,

variations

reported

of food

the

may

interindividual

of vitamin evaluated

supplements.

be a valuable

in the target tissue preferential organs

and bile in the gastrointestinal the carriers for tocopherol

lipoproteins

(16).

considered eligible for this illness and were not taking

protect

epidemiologic E may

radand

long storages. The absorption and utilization ofdifferent micronutrients is influenced by a variety of factors that may interfere with its form before it reaches the plasma. Because a-tocopherol is fat soluble,

and

micronutricnt kinetics properly

influence

drugs

erol concentrations

Sixty-four

the living

is evidence that carcinogenesis

vitamin

(7, 8). activity

its concentration

attention

as vitamin

Several that

agent or therapeutic

certain

the

and clinicians technology (1-6).

effects. There types ofchemical

in some

carcinogens

animal

low-density

stantial

ferent

nutritionists, advances

a complex and

Subjects

scientists, ofimportant

ofdietary poproteins

exerts

as potential candidates for use in large this communication we report the results

Introduction

and

intake

cronutrients

micronutrient

those fed a low-fat diet. The results plasma kinetics of a-tocopherol are of 440, 880, or 1 320 mg d/-a-to-

copherol are given to normal, Nutr 199 1 ;53:723-9.

netics,

in dcpeaked

to the pretreatment concentrations plasma elevation of a-tocopherol

as compared with study indicate that when supplements

KEY

resulted that

Ruppenihal,

presence

(9-1 1). Li(12). Tothe

role

(1 3-15). © 1991 American

of

Food Society

I From the Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI; the Departments of Statistics and Probability, and Food Science and Human Nutrition, Michigan State University; and The Chemoprevention Division ofCancer Control and Prevention Branch, National Cancer Institute, Bethesda, MD. 2 Supported by PHS grant N0l-CN-45 167, awarded by the National Cancer Institute, NIH, DHHS. 3 Address reprint requests to NV Dimitrov, B-220 Life Sciences Building. Michigan State University, East Lansing. MI 48824. Received June 7, 1990. Accepted for publication September 12, 1990.

for Clinical

Nutrition

723

Downloaded from www.ajcn.org by guest on July 10, 2011

which returned 1 2 and 20 d. The

dose

in a steady

800,

mg (400,

of d/-a-tocopherol

for 28 d) resulted

Mary

studied after on different

1320

concentrations

by days 4-5 of supplementation. ment after day 28 was associated tocopherol, between

or

as a single

vation

Giiiland,

volunteers were were ingested

440, 880,

of

in response

724

DIMITROV

did not

follow

taking

a contraceptive

oral

contraceptives exceeding ±20%

weights

All

participants

(including

had

normal

normal

urinalysis

cluding

plasma

program

were

not eligible;

women

a midday

normal-range

dl-a-tocopherol,

leukocyte and

peripheral

differential

blood

count

normal-range

and

platelets).

biochemical of

was

counts A

profile,

in-

high-density-lipoprotein

(LDL) cholesterol, were Determination ofthese variables Laboratory by using automated

methods. For (Roche-Cobra

total and HDL cholesterol the enzymatic method Fara Kit, Diagnostic Chemicals, Monroe, CT)

was

The

accepted LDL

LDL

value

was obtained

by using

(total

cholesterol

HDL

-

cholesterol

All subjects

eligible

to participate

by a physician

before

entrance

entered

the study

after

in the

into

signing

The

an appropriate

on

Safety

accordance

with

at DCCP, Helsinki

NCI.

and

done

in

Declaration.

Roche

of d/-a-tocopherol

Inc,

Nutley,

for vitamin study were IU/d).

the

Butanol-

were

studies

by the

wk intervals

the

studies

and

E at 0800.

daily

schedule. took

single-dose

given

with

a designated The

subjects

capsules

with

three

received Blood

150 mL

monitor,

1 and

from

phosphate Blood

from samples

containing X g for

frozen

at -20

>

subjects

whole

milk

participating skim

were

a single dose of440, samples were collected

in the

concentrations

at 8-

880, or 1 320 mg every 3 h during

solution

dilutions

= 8), 880 mg (n for 28 d. Each subject

only

(no

=

Blood

samples

were

taken

absorption wavelengths

determined

nm for D-a-tocopherol plasma (0.5 mL)

of

and upper

the

an

phosphate

was

ability

in intake

stricted

foods

peanuts,

and

and

unrelated included

to the cereals,

oils (wheat

germ,

vitamin

kale,

E supplements.

almonds,

safflower,

Re-

sunflower

cottonseed,

Known tate

mixture

rapeseed,

(Milford,

sunflower). The

tation

low-fat high-fat

effect was

ofdietary studied

fat on response in

six

diet for 5 d and diet. The other

reverse order. Approximate was 18-24 g. The midday consuming

were

the

low-fat

subjects.

after three

to vitamin Three

an 8-wk subjects

fat content meal provided diet

ate

a fat-free

subjects

rest were consumed ofthe

E supplemenconsumed

a

changed to a the diets in

high-fat breakfast 45 g fat. The subjects

breakfast

followed

into

added

the

was

vortex of

and

HPLC

amounts added

by

S jzm

Isocratic Liquid were used. The

made

for

by dis-

daily.

Actual

ultraviolet

Extinction coefficients for D-a-tocopherol

and and

to a 1 .5 mL

mixed

poly-

the solution

0.05 pro-

This was (I : 1) was

for 60 s. Finally,

dipotassium was

again organic

0.15

monohydrogen vortex

mixed

for 30

1 3 000 X g for I mm. The to a I .5-mL polypropylene

organic micro-

for 1 mm at I 3 000 matrix was directly

apparatus.

of D-a-tocopherol

to 0.50

MA)

prepared

tube; 0.05 mL acetonitrile and solution were added to initiate

solution

centrifuged at was transferred

ofthese compounds and used to generate A Beckman (San

seeds,

at was

was stored

by measuring

acetate. transferred

was

injected

the

sample

and provide the internal standard. 1 5 5, 0.25 mL butanol-ethylacetate

aqueous

then layer

5

studies vari-

from Midwest monohydrogen

in 20 mL acetonitrile. were

nm

weekly

until

ace-

acetate

evacuated

was

daily

determination

in the chronic E to minimize

D-a-tocopherol

acetate

copherol

twice

Burdick and

tubes were centrifuged was removed and

solutions

centrifuge tube and was centrifuged x g. A 0.025-mL sample of this

collected

by the HPLC

oil in 20 mL acetonitrile. The solution was prepared by dissolving

supplementation. for plasma a-to-

were

samples

from

No sample

with a spectrophotometer. used were 75.8/292

and

mL

the

The plasma

ofthe study and twice weekly during last dose was given, blood samples Subjects participating foods rich in vitamin

av-

consuming

methanol

(Pittsburgh). directly into

beginning After the

baseline was reached. were asked to avoid

MI),

evaluation.

propylene microcentrifuge mL D-a-tocopherol acetate

440 mg

before

subject

purchased

NJ),

Scientific drawn

stock

were

43.6/285 Human

23), or I 320 mg (n = 1 8) vitamin E daily was allowed to participate in one treatment

crossover).

of

The

was determined All solvents were

were

D-a-tocopherol

added,

(n

The

of D-a-tocopherol

ofthese

diets containing For chronic

by fat. received

consumed.

skim milk. Blood 1-5 and day 14.

(Muskegon,

#{176}C for later

tein precipitation vortex mixed for

group

ethylacetate

Fisher were

beginning ofthe study and averaged to produce a baseline value. During the 24-h hospitalization period, the subjects consumed kcal with 38% provided three groups of subjects

days.

lithium heparin. 10 mm and the

wk. The stock

Serial

24 h and daily thereafter until baseline was reached. samples were taken for 2 consecutive days before the

I 770 studies

ingestion self-selected.

2

100%

milk.

hospitalized

of all foods

JT Baker(Phillipsburg,

tubes I 500

vehicle

assuring

were

5 diet

Laboratories

400 mg crystalline

low-fat-diet

the first Baseline

by Hoffmann-La

contained

h after

meals

concentration and Lester (25).

capsules supervised with

vitamin

capsules

for the

solving 100 mg D-a-tocopherol D-a-tocopherol acetate stock

compliance For

Placebo

supplied

daily

E, which was soybean oil. The doses used in this 440, 880, and 1320 mg/d (400 lU, 800lU, and 1200

The

(6 g fat)

NJ.

were

records

6-8

of the

and BHT from Sigma (St Louis), absolute ethanol Solvent Company (Pekin, IL), and dipotassium

Inthe

Protoco/ Capsules

daily

considered compliance

within

diet took the capsule with before breakfast on days

Jackson

tonitrile

on Research University and were

kept

meals

was

If 100%

erage total daily intake for the low-fat diet was 1840 kcal with 25% provided by fat; intake for the high-fat diet was 2410 kcal with 43% provided by fat. All participants received 880 mg dl-

grade.

evaluated participants

All studies

remainder

days

mL water

and

D-a-tocopherol

to correspond

in the plasma. The standards a daily standard curve. Ramon, CA) 1 lOB pump C18

bondapak

Chromatograph, mobile phase

ace-

to concentrations

column.

were

extracted

with

a Waters

a Beckman

and a Beckman was methanol-water

427

331

Integrator (95:5) at a

flowrate of 2.5 mL/min. Peak identification was made by comparing retention times to times for known standards. Peak areas were measured and the ratio of D-a-tocopherol to D-a-tocopherol acetate was obtained for several standards. The ordinate

was

D-a-tocopherol:D-a-tocopherol

acetate

and

the ab-

Downloaded from www.ajcn.org by guest on July 10, 2011

Committee

two

the

Plasma a-tocopherol method of Nierenberg

informed-consent

by the University Committee Subjects at Michigan State

for

Five

information.

Methods

a generally

were

the study.

form approved volving Human

the

trial

Participants

‘--6 g fat.

the needed

maintained

the low-fat were taken

triglyceridcs)/5

-

providing

to obtain

a-tocopherol

formula =

meal

sufficient

concentrations

(24).

AL

were eligible. Individuals with body ofdesirable body weight were excluded.

(HDL) and low-density-lipoprotein prerequisites for participation. was done in the Clinical Center

used

ET

SUPPLEMENTATION scissa

represented

concentration

ear-regression The

lines

correlation

standard

were

AND

of D-a-tocopherol.

calculated

coefficient

Best-fit

by using

was calculated

linear

to be

116.1

for each

92.88

curve.

We

used

change method

intralaboratory,

intrainstitutional,

methods for quality control. The was 2.7% and for the interday

we are participating organized

quality-control

Institute

440

outside-ex-

ofStandards

46.44

program

and

Technology

23.22

MD).

116.1

Statistics No statistical to the

assessments

single-dose

plasma

ofsignificance

study,

the multiple-dose

which

studies,

rate

were

paired-difference

with

times

the

statistic,

t

the

Inc,

Chicago).

For

in a-tocopherol

for

a group

on

Wilcoxon

sta-

analysis

of

(SPSS/PS,

of a-tocopherol

at any given time between groups rates were made with the t statistic. to indicate statistical significance.

plasma receiving P values

contwo <

dif0.05

46.44

23.22

a. 0 116.1

I-. 1320

Three

experiments kinetic

were

response

or

1 320

conducted.

to

mg.

The dose,

a single

The

second

first

the

estimated

dose

estimated

the

being

440,

880,

administered daily over 28 d. The third estimated the effect (low fat vs high fat) on the responses. A total of64 subjects

was involved. Three individuals did were not included in the evaluation. pleted

within

Plasma

doses

at

‘

not complete All experiments

response

to

of

12-24

of a-tocopherol

440,

880,

h after

and

increased

1 320

ingestion

mg

23.22

0

the study and were com-

1 y.

concentrations

single

the

46.44

either

doses ofdiet

in response

vitamin

E with

the

6

3

related. For the other did not vary directly

baseline

values

with

dose.

administration

dose

the most

striking

the

same

baseline shown).

conditions,

plasma

concentration the

chronic

studies

E were

subjects, measured

respectively. Plasma at 0, 4, 7, 10, 14,

shown

given

in Figure curves,

tocopherol 28 d (Fig

remained 2). There

erage responses surement day.

minor

but

the

ofplacebo

were

was

sustained

at

(data

not

days

a-tocopherol 18, 21, 25, large

average

880, and 1320 mg to 8, 23, and 18

concentrations 35, 42, and

28,

interindividual plasma

relatively stable were no significant

under

deviations

of 440,

doses

for 28 consecutive

2. There

in response

only

daily

vitamin

single

a-tocopherol

with

were 48 d as

variations

concentrations

of a-

over the period from differences between

for different treatment To describe the average

groups response

4 to av-

for each meafor each group,

the average increase over baseline values was calculated for all subjects in the treatment group by using values for experimental days 4-28. The average increases for 440, 880, and I 320 mg were

14.4,

14.6,

and

14.9

erage baseline value was was ---80% and was similar in each

regimen

showed

Mmol/L,

respectively.

1 7.2 Mmol/L, for all groups. plasma

72

48

‘

96

120

1). For one individual

(Figure

ofa

82124

FIG I . Distribution ofplasma concentrations ofa-tocopherol in three normal individuals ingesting 440, 880, or 1320 mg a-tocopherol as a single dose (crossover design).

of the increase was dose magnitude ofthe increases

After

91215

Hours

the magnitude individuals the

In

MC

69.66

plasma

peak

69.66

92.88

Results

to

880 MC

E

a given

The

on repeated-measures statistical significance

..j92.88 0

statistic.

I

paired-difference

Comparisons

in regard

subjects.

Because

the average The typical

concentrations

the avincrease response

returning

d after

features

supplementation

ofthe

data

(crossover

design).

1 . The

kinetics

Day-to-day

showed

tions ofa-tocopherol regimen. Therefore, subject-diet centration

the averages

difference cance, P

=

effect was

statistic icance.

ofaverage was obtained.

presented

in Table

plasma

increase When

was assessed

statistic. The completed design, with the response

was

significant

not

showed

(P

=

significant

(P

=

should be divided The data support

0.07).

of day-

concentra-

after -‘-2 d on a multiple-dose across days 2-5 in Table

for the two diets

creases over days 2-5, diets was not significant order

are

elevated

that 0.50),

(P The

1, a

in plasma conthe difference a paired

with

t statistic, the result was one-sided statistical 0.05. The same significance was calculated

Wilcoxon crossover

One

was the large

on a given regimen. a-tocopherol was inof two different diets

changes average

are reached by averaging

specific measure of a-tocopherol

between

paired of the

that

ceased.

analyzed

to-day variation in responses for individuals The effect of fat in the diet on plasma vestigated by using six subjects on each

diet to

12-20

signififrom the

analysis of variance being the average in-

the effect of the order of the the subject effect on top of =

0.56), last

and

P value

the effect based

by two to assess the one-sided the conclusion that administration

of the

on the

F

signifof

Downloaded from www.ajcn.org by guest on July 10, 2011

SPSS

made

three

paired-difference

tistic, and the F statistic based variance were used to assess centrations ferent dose were taken

only

comparisons

between

made

were

involved

pairwise

concentrations

dose

MC

69.66

intraday CV for HPLC was 4.9%. In addition,

in the round-robin

by the National

(Gaithersburg,

and

725

a-TOCOPHEROL

lin-

regression. 0.99

>

PLASMA

726

DIMITROV

ET

AL

triglyceride -J

40.63 34.83

-

29.02

-

subject values

-I

0

3, the 23.22

-

in the range

of intrinsic

17.42

-

11.61

-

pattern

to cholesterol.

of plasma

has been

a

we converted the plasma with 440 mg vitamin El

As presented

a-tocopherol

concentrations

in Figure expressed

as imol/L is similar to that expressed as the ratio of a-tocopherol to cholesterol. However, a-tocopherol:cholesterol appears to have a CV similar to that for the ratio of a-tocopherol to amount of plasma.

0

8

were

of discussion and controversy, obtained from supplementation

d to a ratio ofa-tocopherol

‘U I 0.

but they

variations and showed no significant trend. Because the expression of a-tocopherol in plasma

0

E

concentrations,

random

1

5

10

1

1

15

20

1

25

Discussion 30

35

40

45

50

Days

1

0

E 1

0

that oral administration ofa-tocopherol in substantial interindividual variations

‘U I 0.

(Fig

0

8

1). Such

tocopherol

I-.

inter-

and

as a single dose resulted in plasma concentrations

intraindividual

concentrations

variations

were observed

20). Tangney et al (17) warned that variations in measurements of plasma

by other

in plasma

intra- and interindividual a-tocopherol should

(17,

a-

investigators be

carefully

considered when conducting clinical trials. Use of a single or a few measurements of plasma values during the cxccution of clinical trials could be misleading. Various factors may contribute to intra- and interindividual

Days

variability.

Use

of capsules Procedures

excluded compliance violations for administering supplements

strictly

2. Top:

in eight

normal,

Distribution healthy

of plasma subjects

ingesting

concentrations

concentrations 440

of a-tocopherol mg

a-tocopherol/d

for

indicates discontinuation of a-tocopherol supplementation. Bars represent SEMs. Middle: Distribution of plasma concentrations of a-tocopherol in 23 normal, healthy subjects ingesting 880 mg a-tocopherol/d for 28 consecutive days. Bottom: Distribution ofplasma concentrations ofa-tocopherol in 18 normal, healthy subjects ingesting 1320 mg a-tocopherol/d for 28 consecutive days. 28 consecutive

days.

The

To

monitor

provide

who

uniformity

witnessed

the ingestion

as a possible factor. in this study were during

ingestion

of

the vitamin, all subjects took the vitamin with milk. In addition, the capsules were always taken in the morning followed immediately by breakfast. We believe these procedures facilitated both the disintegration of the capsule and absorption of the vitamin, both ofwhich arc factors that might influence variability in responses (16). Similarly, a strictly uniform schedule of blood collection was used in an attempt to minimize variability. The choice ofpreparation does not appear to be a contributing factor. We chose d/-a-tocopherol because Baker et al (20) demonstrated that administration of high doses ofthis form resulted in higher

Days FIG

controlled.

of a study

arrow

etate form. a-tocopheryl tions

of plasma

tocopherol

as compared

with

the

ac-

Administering smaller doses of free a-tocopherol or acetate resulted in equal plasma concentra-

(12).

Age, sex, menstrual status, and body composition are additional factors that could contribute to the variability of responses. Evaluation of such variables was not possible in this study and would require a specific design involving a larger number of subjects.

880 mg vitamin average plasma same lipids within

E for 5 d and concentrations

the high-fat diet of a-tocopherol

resulted than

in higher does the

dose of vitamin E taken with a low-fat diet. The plasma measured before and at the end of the study remained the normal ranges. Some changes were noticed in the

Because absorption of vitamin E is influenced by the amount ofdietary fat (9, 26), the effect ofdietary fat on plasma responses to vitamin E supplementation was evaluated. Our results showed that an increase oftotal fat intake in breakfast and lunch meals was sufficient to produce a significantly higher increase in plasma a-tocophcrol concentration during supplementation with 880 mg vitamin E for 5 consecutive days (Table 1). How much of

Downloaded from www.ajcn.org by guest on July 10, 2011

Use of pharmacological doses of a-tocopherol for prevention ofcancer and other clinical purposes requires knowledge of factors that influence its bioavailability and concentration in plasma or target tissues. Because the vitamin is consumed as a constituent ofa regular diet and is also normally found in plasma and tissues, kinetic and bioavailability studies of supplemental atocopherol are often difficult to interpret. Our results showed

SUPPLEMENTATION TABLE

AND

PLASMA

727

a-TOCOPHEROL

1

Plasma

concentrations

of a-tocopherol Day

Average Subjects

lt

2

3

4

5

14

over baseline, days 2-5

mo//L

L H

18.11

20.90

25.08

12.07

23.68

16.25

2.32

16.71

22.29

18.58

38.08

18.11

19.5

7.66

L

17.65

24.15

33.44

H

13.00

19.50

30.19

39.00 18.58

36.22 14.40

18.58 11.61

15.56 7.66

L H

15.79 11.61

30.65 25.08

29.72 33.9

25.08 40.87

25.08 71.52

18.58 10.68

11.84 31.35

L H

11.61

16.72

19.5

22.29

31.58

11.14

10.91

13.00

35.29

38.08

40.87

35.29

18.11

24.38

14.86 68.73

12.07 71.05

23.22 19.5

0.23 46.44

2

3

4

5

13.93

14.86

H

22.29

34.83

14.86 100.31

L

15.32

24.61

27.86

9.98

9.29

9.29

2.55

H

12.07

29.72

20.43

27.86

43.65

21.36

18.34

6.73 13.00

25.31

6

Average over baseline

L H S

-

L, low-fat

diet;

H, high-fat

diet.

9.75

880 mg a-tocopherol/d

5.34

7.66 27.40

24.15

given

0.93 1.86

for 5 d.

t Baseline.

that

increase

and

how much

is due

to increased

contributed

absorption

of the

to the a-tocopherol

the fat provided

with

that that

of tocopherol absorbed could secreted by the liver increases

the amount the amount

is being

secreted

in a specially

Lehmann a-tocopherol

designed

in plasma actually

ate

has been reported ncr of a-tocopherol

may

to the liver

possibility

is that

endogenously

absorption

of the

a-tocopherol

that

or

mg

1 320

in the

The

should

present

diet

subjects This

be dc-

study

produced

observation,

nontoxic during a-tocopherol,

This

by a different

possibility

secreted with most

daily the

and

questioned

the incorporation of a(12, 30, 3 1). A remote fat may

a fat-free

play

a role

or low-fat

in

diet.

critical issue related to use of agent relates to the most effective

schedule chronic

route

has been

of administration.

Our

administration

of 440,

880,

plasma

con-

patterns

of average

d. Although

results

were

similar

observations

et al (20)

using

for

the

in chronic 400 and

three

different

studies

were

re-

800 mg d/-a-tocophcrol/

higher

plasma concentrations were observed with was done with few participants(six per group) and a limited number of measurements. In addition, at days 15 and 22 no differences related to the different dosages were found among experimental groups. Similar variations occurred in the mg, the study

1600

reported

centrations

erol

is not the 1). Part

vitamin

2). Similar

by Baker

threefold

which

27-3

of the

(Fig

studies

an

in the low-fat

transport ofa-tocopherol and utilization (12,

evidence that is preferential

At present, perhaps the vitamin E as a chemopreventive

practical

same but more fat

also

a low-fat

be absorbed

(32).

now is good in lipoproteins

indicate

be the because

doses ported

possibility

also reported higher to high fat consumption

breakfast.

and there tocopherol

and

from

by others, raises questions regarding the manabsorption and transport. It may be spec-

a-tocopherol

transported

with

concentrations. a fat-free

The

lipoproteins

However,

even

ulated that the chylomicron only pathway for its transport of the

be determined.

et al (26) related

study.

of a-tocopherol

increase group

cannot

in very-low-density

considered (27). vations in plasma ingestion

diet

centrations

supplement

absorbed

by

Brim

reported above

et al (23).

by

these

baseline

even

Plasma

authors when

a-tocophcrol

con-

rose

than

never

mcga

doses

more

of d/-a-tocoph-

mg) were given. London et al (33), using doses of mg, and 546 mg vitamin E/d for 60 d, observed no significant differences in serum tocophcrol concentrations measured at day 60. These authors did not study kinetic patterns between day 1 and day 60, the last treatment day. B#{246}hles (34) I 36.5

(3000 mg,

273

studied plasma cragc age 23.5 acetatc/d

and

tocopherol

y) using found

200,

similar

concentrations 400, and increases

in young

males

(av-

800 mg d/-a-tocophcrol in plasma

concentrations.

The lack ofdose-response relationship observed in these studies may also be due to a decrease in absorption as a result of the increase in ingested dose (35). The pattern ofsinglc-dose kinetics during the first 24 h in our study resembled those found by Baker ct al (20) using 400, 800, and 1600 mg d/-a-tocopherol as well as the results of Horwitt et al (21) using a dose of 880 mg. Use of daily doses of micronutrients appears to be practical and easy to implement (36).

Downloaded from www.ajcn.org by guest on July 10, 2011

L

728

DIMITROV

ET

AL

(41).

It is obvious

question. As with

that

other

a consensus

fat-soluble

ical trials, the concept lenged. The investigators never

addressed

the

and

optimal

time

lack

of information

the planning expectations

of human dubious.

studies

with

could

be useful

not

in this

00

question

direction

this in din-

concentration

of cancer. trials

micronutrients

in the

for those

practicing different

should

area

population

clinical

as well.

preparations

the makes

difficult and the obtained from

normal

designing

physicians

Thus,

in that

chemopreventive trials However, the information

using

combinations

used

plasma

prevention

preclinical

only

and

resolve

already

of optimal for

from

for nutritionists III

micronutrients

to

of target concentration remains unchalinvolved in preclinical studies have

needed

kinetic

is needed

trials

Further

and

but

studies

micronutrient

be encouraged.

13

o,.:l

References

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FIG 3. Comparison of plasma cx-tocopherol concentrations ratio of a-tocopherol to cholesterol. This is the same group Figure 2 (440 mg for 28 d). The arrows indicate discontinuation tocopherol supplementation. Bars represent SEMs.

with

the

shown

in

of a-

Because toxicity for the doses used in this study is not a problem, the main question that remains is selection ofthe most effective dose

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