Lack of effect of chronic administration on serum cholesterol and triglyceride W Nierenberg,

ABSTRACT

T Bayrd,

Previous studies of retinol and other

ministration plasma

Garrett

triglyceride

administration to retinol,

on

suggest retinoids

concentrations.

of 9-carotene, plasma lipid

and

The

effects

over study

were

randomly

assigned

placebo

mg

$-carotene/d

orally

(n

carotene. groups; ±

Retinol $-carotene

47 nmol/L

either

3 1). At study

=

in the

placebo

of chronic

oral

12 mo while they in which patients

(n

entry

30) or 50

=

and

1 y later,

obtained for measurement HDL cholesterol, retinol,

concentrations concentration

changed increased group

adof

partially metabolized have not been well

studied; therefore, we studied 61 subjects were enrolled in a skin-cancer-prevention

fasting blood samples were glycerides, total cholesterol,

A Stukel

that chronic oral causes elevation

a carotenoid concentrations

to receive

Therese

and

of triand f-

minimally an average 4279

± 657

in both of I 2.1 nmol/L

in

the active-treatment group. small increases in triglyceride

Both groups experienced similar and total cholesterol concentrations

and

small

cholesterol.

tion

of

decreases 50

mg

in HDL f3-carotene/d

concentrations.

Am

KEY WORDS

fl-carotene,

plasma,

Daily

did

J C/in Nutr

not

oral

affect

administraplasma

lipid

199 l;53:652-4.

retinol,

triglyceride,

cholesterol,

Little

is known

ministration showed

no difference

sity-lipoprotein

a placebo triglyceride

study

studies, dietary epidemiologic studies, studies, it has been postulated that

oral fl-carotene may have cancer-chemopreventive properties (1, 2). When used in high doses, retinol and several other retinoids have also shown promise in this regard for certain types of tuHowever, use may be limited

One adverse is an increase Although

of these by their

the mechanism

(7,

compounds considerable

as cancer-preventive

clinical

effect ofretinoids that has been in serum or plasma triglyceride

centrations oftriglycerides of high doses of retinol for acne

8, 10-12),

ofthis

effect

etretinate

(3-6).

or high-

no

concerning of concern study found chronic oral

consistent

changes

in

were noted (20); the small seasonal effect made further

conducting

oral

secutively

by one

Subjects

and

a randomized

fl-carotene

prevents

clinical

trial

nonmelanoma

to

skin

can-

we report the changes in serum lipid in a subset of 66 patients enrolled

concon-

of us (GTB)

in this

trial.

methods

patients,

increased

con-

during administration ( 1 3-cis retinoic acid) for psoriasis

(8,

13). Betaoral din-

ically important 1 8). However,

(14hy-

increases in plasma retinol concentrations because the mechanism of retinoid-induced

pertriglyceridemia chronic supplementation in plasma triglyceride

is unclear,

there

with a-carotene concentrations.

is reason

for

could

concern

cause

that

elevations

Am J C/in Nutr

199I;53:652-4.

one

multicenter from

all of whom

the

in detail Group the

tamed

and

a total-body

blood

specimens

I

patient’s were

and lipid cholesterol). for 48 h and

From

the Division

study.

Inc.

visit, (at 0800)

determinations Patients food

for

of Clinical

treated

study

informed

were

methods

was

Review

examination

drawn

been

The

Institutional

initial skin

previously

carcinoma, were enrolled Inc. clinic as a part ofa large

( 14). Permission

elsewhere

Health,

neapolis. During

alcohol

had

basal- or squamous-cell in the Group Health,

skin-cancer-prevention

are described

/3-carotene, and HDL

well documented concentrations.

is unclear,

were observed (7-9), isotretinoin and

toxicity

carotene is partially converted to retinol, although daily supplementation with 50 mg fl-carotene does not produce

652

3-carotene,

In this paper occurring

for at least consecutively

the basis of animal serologic epidemiologic

mors. agents

(LDL),

in five volunteers receiving five similar volunteers re-

provided no data the main lipid

concentrations and a possible

currently

whether

cer (14). centrations

of very-low-den-

of retinoids. A more recent with protoporphyria received with

adstudy

difficult.

are

Sixty-six

and

(19). That study concentrations,

triglyceride of subjects

We

(-carotene A previous

concentrations

(HDL) cholesterol compared with

supplementation

interpretation

of chronic

low-density-lipoprotein

during administration that when 1 3 patients plasma number

effects

concentrations.

in mean

(VLDL),

density-lipoprotein 1 80 mg /3-carotene/d ceiving plasma

the lipid

lipid

Introduction On

about

on plasma

obtained

Board

consent

was

was performed. at study

entry

(cholesterol, required

16 h before Pharmacology

the

Mmob-

Fasting for retinol,

triglycerides, to abstain from venipuncture.

and

the Department

ofCommunity and Family Medicine (Biostatistics), Dartmouth Medical School, Hanover, NH, and the Department ofDermatology, University of Minnesota, Minneapolis. 2 Supported in part by NCI grants CA32934 and CA23 108. 3 Address reprint requests to DW Nierenberg, Division of Clinical Pharmacology, Hinman Box 7650, Dartmouth Medical School, Hanover. NH 03756. Received March 21, 1990. Accepted for publication July 20. 1990. Printed

in USA.

© 1991 American

Society

for Clinical

Nutrition

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/3/652/4731842 by EKU Libraries user on 30 January 2019

David

of oral fi-carotene concentrations13

EFFECTS Patients mate poor

again

received

cer and fasting whom complete Whole taming l0-mL

a total-body

blood data

blood

was

after

collected

and

stored

removed

and

brief,

both

assays the

system. step.

assays

matrix were

mobile

phases

directly

consisting precision was

by the National

(formerly

dard)

the

/3-carotene, were

obtained

Serum total concentrations

by the

Institute

from

Control

(used

Chemical

cholesterol, HDL were determined

of our Program

and

ad-

TechnolCrystalline

as an internal Co.

cholesterol, by using

stan-

St Louis.

and triglyceride techniques and re-

agents designed for use with a Baxter Paramax instrument (Baxter Paramax Systems Division, Irvine, CA). The assays for total cholesterol and HDL cholesterol involved the use ofa technique based on a modification ofthe measure cholesterol associated were first separated from other polyanionic

precipitation

ofphosphotungstate measured

with

Chemistry McGaw

Systems Park, IL).

participation by the College An plasma

by using

a technique

cedure ofStavropoulis and daily quality

method ofAllain et al (23). To with HDL cholesterol, HDL’s serum lipoproteins by isoelectric-

Serum

(24).

the

precipitating

triglyceride

based

I y. All statistical

tests

was

were

used in the performed

of the

Supply

in the Proficiency Testing of American Pathologists.

independent t test lipid concentrations

were pro-

Solutions for calibration from American Dade

(American Hospital Accuracy was further

assessed

Corporation, by laboratory

Program

administered

to compare two groups at the

the changes in of patients over 0.05

level

of sig-

Results Of the

66 patients

complete

data

available

enrolled

in the

who received The remaining for retinol,

study,

423

were

± 54 nmol/L

concentrations

HDL

between

cholesterol

the values and

at baseline

are also given.

cholesterol

and

in the

icantly 0.45

between mmol/L

and

8 in the

the two occurred treatment

cho-

1 y; the

Clinically

small were

groups. Increases in 12 subjects,

12.1

total

at

concentrations

462

were

4279 ± 657 nmol/L, respectively. 1 reports the concentrations of triglycerides, and

>

complete

The ±

baseline

126 nmol/L)

L) in these

differ-

increases

observed

in were signif-

in serum triglycerides 4 in the placebo group

group.

in our

study

sites

plasma ± SD),

concentrations

of retinol

and

(462

f3-carotene

6 I subjects

found

were

multicenter

(26).

In this

Thus,

this

representative

in the placebo group

reported

in our

plementation

(24

larger

with

population

of subjects,

values at four

the

baseline

of 6 1 subjects

In addition,

group

groups

were

of subjects

placebo

appears

changes

in retinol

147 ± 59 nmol/L)

(-

(-7.7

or fl-carotene (38. 1 ± 1 5.7 nmol/L) increase in fl-carotene in the placebo L) and the very large (4279 ± 657 nmol/L)

baseline

was 4 19 ± 344 nmol/L (1 concentration was 2447 ± 600

± 91 nmol/L)

either

2580

± 54 nmol/

176 1 subjects

group

group.

the

± 80 and 423

mean

of a subgroup

larger

concentration treatment

to

involving

larger

study

ofour

(2346

± 71 and

similar

trial

/3-carotene concentration and the baseline retinol

nmol/L.

similar

after

and

in

to changes

1 y of oral

± 16. 1 nmol/L;

sup-

I ± SD)

( 14). Finally, group

the negligible (12. 1 ± 4.7 nmol/

increase in fl-carotene were similar to results

in the treated group found in our larger

of subjects

(14).

Thus,

we believe

data

TABLE I Plasma triglyceride, cholesterol, and HDL-cholesterol in placebo (n = 30) and fl-carotene (n = 31) groups I y and the differences between these values5 Baseline

Triglycerides fl-carotene Placebo Total cholesterol /3-carotene Placebo HDL cholesterol /3-carotene Placebo

this

subset

of 61

or serum

concentrations at baseline and at

1y

Difference

1.30 ± 0.14 1.21 ±0.10

1.49 ± 0.14 1.36±0.12

0.19 0.14

±

5.53 ± 0.23 5.41 ±0.19

5.84 ± 0.20 5.85±0.18

0.30 0.43

± 0. I 3 ±0.llt

I .30 1.37

1.26 1.30

± ±

0.09 0.08

± ±

0.08 0.07

-0.04 -0.07

0.07 ±0.07t

± ±

0.04 0.05

were

fl-carotene and 30 patients five patients did not have /-carotene,

and

in /3-carotene

(P

groups

nmo//L

nificance.

available for 3 1 patients who received placebo.

two

concentrations

properties

concentrations

on a modification

and Crouch (25). control were obtained

the

1 y were changes

both groups whereas small decreases in HDL cholesterol observed in both groups. None of these changes differed

iso-

between-day 7%. Accuracy

of Standards).

acetate

Sigma


1.05 with two previous

larger

observations

group.

supplementation

produce

of chronic

find-

that

oral

adverse

therapy

with

retinoids.

These

observations

involving

are

relevant

fl-carotene.

sociated

with

including

oral

in the

Because

are treated in such trials, for this role have minimal

administration

elevation

not associated and

ofthe

approved

with because

profile

to be minimal

concentrations and

Food

and

Drug

effects

fl-carotene

ofeither

retinol

by this

agent.

both its potential efficacy toxicities resulting from

under

way

or

(FDA)agent

attractive

should help clarify as well as potential ministration.

for statistical

limit

Administration

cancer-preventive

We thank ER Greenberg

Studies

retinoids,

orally for cancer of fl-carotene is

caused

remains

other

concentration,

administered administration

the

of patients

that agents considered various side effects as-

triglyceride

increased

of prevention

numbers

of retinol

plasma

of adverse (27),

context

large

it is essential toxicity. The

the applicability of these agents prevention. However, because lipids,

the

we looked

8 receiving

receiving

20).

in serum

between about

lack

in patients

(180

increased in serum

whose triglyceride concentrations increased This increase occurred in 12 ofour 61 sub-

documented

glycerides

trials

or /3-

of patients

appears

as a potential with

fl-carotene

for this indication, long-term oral ad-

8. Windhorst DB, Nigra T. General clinical toxicology oforal retinoids. J Am Acad Dermatol 1982;6:675-82. 9. Dicken CH. Elevation of blood triglyceride levels secondary to administration of vitamin A. Arch Dermatol l98l;l 17:189-90. 10. Lyons F, Laker MF, Marsden JR, Manuel R, Shuster S. Effect of oral 13-cis-retinoic acid on serum lipids. Br J Dermatol 1982;107: 59 1-5. 1 1. Bershad 5, Rubinstein A, Paterniti JR Jr. et al. Changes in plasma lipids and lipoproteins during isotretinoin therapy for acne. N Engl J Med 1985;313:981-5. 12. Katz RA, Jorgensen H, Nigra TP. Elevation of serum triglyceride levels from oral isotretinoin in disorders in keratinization. Arch Dermatol l980;l 16:1369-72. 13. Gollnick H. Elevated levels of triglycerides in patients with skin disease treated with oral aromatic retinoid: the significance of risk factors. In: Orfanos CE, Braun-Falco 0, Farber EM, Grupper C, Polano MD, Schuppli R, eds. Retinoids: advances in basic research and therapy. Berlin: Springer-Verlag, I 981:503-5. 14. Greenberg ER, Baron JA, Stevens MM, et al. The skin cancer prevention study: design ofa clinical trial ofbeta-carotene among persons at high risk for nonmelanoma skin cancer. Controlled Clin Trials 1989; 10:153-66. 15. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, et al. Beta-carotene as an oral photoprotective agent in erythropoietic protoporphyria. JAMA l974;228: 1004-8. 16. Willett WC, Stampfer Mi, Underwood BA, et al. Vitamins A, E, and carotene: effects ofsupplementation on their plasma levels. Am J Clin Nutr l983;38:559-66. 17. Dimitrov NK, Meyer C, Ullrey DE, et al. Bioavailability of betacarotene in humans. Am J Clin Nutr l988;48:298-304. 18. Constantino JP, Kuller LH, Begg L, et al. Serum level changes after administration ofa pharmacologic dose ofbeta-carotene. Am J CIin Nutr 1988;48: 1277-83. 19. Mathews-Roth MM, Gulbrandsen CL. Transport of beta-carotene in serum of individuals with carotenemia. Clin Chem 1974;20: 1578-9. 20. Poh-Fitzpatrick MB, Palmer RH. Elevated plasma triglyceride levels are associated with human protoporphyria. J Lab Gin Med l984;104:

B for his many

useful

comments

and Bi Dam

257-63. 2 1 . Nierenberg

analyses. 22.

References 1. Peto R, Doll R, Buckley JD, Sporn MB. Can dietary beta-carotene materially reduce human cancer rates? Nature 198 l;290:201-8. 2. Moon TE, Micozzi MS, eds. Nutrition and cancer prevention: investigating the role of micronutrients. New York: Marcel Dekker Inc, 1989. 3. Goodman DS. Vitamin A and retinoids in health and disease. N EnglJ Med l984;3l0:1023-3l. 4. Sporn MB, Roberts AB. Role ofretinoids in differentiation and carcinogenesis. Cancer Res l983;43:3034-40. 5. Moon RC, McCormick DL, Mehta RG. Inhibition of carcinogenesis by retinoids. Cancer Res [Suppl] 1983;43:469s-75s. 6. Boyd AS. An overview of the retinoids. Am J Med 1989;86:56874. 7. Gerber LE, Erdman JW Jr. Changes in lipid metabolism during retinoid administration. J Am Acad Dermatol 1982;6:664-72.

23.

24.

25.

26.

27.

DW. Determination ofserum and plasma concentrations of retinol using high performance liquid chromatography. J Chromatogr 1984;31 1:239-48. Nierenberg DW. Serum and plasma beta-carotene levels measured with an improved method of high performance liquid chromatography. J Chromatogr l985;339:273-84. Allain CC, Poon IS, Chan CSG, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem l974;20: 470-5. Burstein M, Scholnick HR. Morfin R. Rapid method for the isolation oflipoproteins from human serum by precipitation with polyanions. J Lipid Res 1970;l 1:583-95. Stavropoulis WS, Crouch RD. A new colorimetric procedure for the determination of serum triglycerides. Clin Chem 1974;8: 857(abstr). Nierenberg DW, Stukel TA, Baron JA, Dam BJ, Greenberg ER, the Skin Cancer Prevention Study Group. Determinants of plasma levels ofbeta-carotene and retinol. Am J Epidemiol I989;130:Sl 1-21. Barnhart ER. Physicians desk reference. 44th ed. Oradell, NJ: Medical Economics Company, Inc, 1990.

Downloaded from https://academic.oup.com/ajcn/article-abstract/53/3/652/4731842 by EKU Libraries user on 30 January 2019

(4 receiving

several

placebo

group

changes

concentrations,

the 61 subjects did triglyceride mmol/L. These observations studies

larger

of fl-carotene

10-fold,

in triglyceride

jects

with

to a much

described.

Although

creases

supplementation

fashion

ET AL