Lewis D Stegink, Edward F Bell,

Thomas

Twelve normal adult subjects 0. 136 mmol aspartame/kg On 1 study day the beverage

ABSTRACT

erage providing different days. aspartame,

Marvin C Brummel, and Ekhard E Ziegler

on the other

the beverage

J Persoon,

ingested body

wt

provided

provided

both

Lloyd

a bevon 2 only

aspartame

(AUC)

difference

for

phenylalanine

between

groups

(197

also

showed

± 49.1

vs

no

182

significant

± 28.3

mol.

L . h for aspartame alone and aspartame plus sucrose, respectively). Similarly, the high mean ratio ofphenylalanine to large neutral amino acids (Phe:LNAA) in plasma did not differ significantly (0.265 ± 0.046 for aspartame alone, 0.275 ± 0.107 for aspartame plus sucrose). However, there was a small but significant difference between groups for the 4-h AUC values for plasma Phe:LNAA. The simultaneous ingestion of sucrose with aspartame had only minor effects on aspartame’s metabolic disposition. Am J Clin Nutr 1990;52:335-4 1.

KEY WORDS

Aspartame,

phenylalanine,

sucrose

Introduction Aspartame (APM; N-a-L-aspartyl-L-phenylalanine methyl ester) is a widely used dipeptide sweetener. Upon oral ingestion APM is metabolized to release aspartate, phenylalanine, and methanol to the portal blood (I, 2). Concerns have been raised that aspartame ingestion may increase plasma phenylabanine concentrations to concentrations that are potentially hazardous.

For

example,

children

with

untreated

phenylketonuria

have grossly elevated plasma phenylalanine concentrations and most of these children are mentally retarded (3-7). Thus, it is important to ascertain whether the plasma phenylalanine concentration achieved at ingestion of usual amounts of APM is similar to values known to be associated with deleterious results in children with phenylketonuria. We (1, 2) previously showed that the high mean plasma phenylalanine

concentration

administered. concentration is affected

plasma

However, resulting by a number

phenylalanine

Am J C/in Nuir

1990;52:335-4l.

is proportional

to the

dose

of AFM

of factors.

concentration

Printed

For

example,

the

is lower

when

in USA.

© 1990

high

mean

much

Society

a meal

than

when

it is ingested

alone

in orange

larger

change

in Phe:LNAA

than

would

be observed

with

AFM alone. Our objective was to examine the effect of carbohydrate on the metabolic distribution of APM by measuring plasma amino acid, glucose, and insulin concentrations in nor-

From the Departments University

oflowa

2 Supported

College

Address

reprint

and

Biochemistry,

City,

IA 52242.

for Clinical

ofPediatrics,

Biochemistry,

ofMedicine,

Iowa City.

in part by grant

search Centers Program, stitutes of Health, and pany, Deerfield, IL.

Received Accepted

an APM

American

with

juice (8). Concerns have been raised about the effects of simultaneous ingestion ofcarbohydrate with AFM (1 1-1 3). These investigators suggested that simple evaluation ofthe high mean plasma phenylalanine concentration produced by AFM ingestion may underestimate the potential for harmful effects because such evaluation ignores interactions of phenylalanine with other amino acids that are transported into brain. Fhenylalanine is transported from the plasma into brain via an amino acid transport site that is shared by several otherlarge neutral amino acids (LNAAs; methionine, isoleucine, leucine, valine, tyrosine, and tryptophan). Transport kinetics follow the rules of competitive inhibition. Thus, the quantity of a specific amino acid transported into brain increases as its concentration in the plasma increases. However, because each amino acid in the group competes for transport with other members ofthe group, the transport of a specific amino acid increases in proportion to its plasma concentration only ifthe concentrations of other amino acids sharing the transport site remain constant. Carbohydrate ingestion is known to decrease plasma concentrations of vabine, isoleucine, and leucine. Because these three amino acids comprise a major part ofthe denominator ofthe phenylalanine-to-LNAA molar-concentration ratio (Fhe:LNAA), ingestion of APM with carbohydrate was predicted to produce a

3

the high mean plasma phenylalanine from ingestion ofa specific APM dose

Jr,

dose is administered in portions rather than as a single bolus (8-10). Similarly, the high mean plasma phenylalanine concentration is bower when the equivalent dose of APM is ingested

and 3.5 1 mmol sucrose/kg body wt. The high mean plasma phenylabanine concentrations were similar after administration of aspartame alone (158 ± 28.9 mob/L, I ± SD) and administration of aspartame plus sucrose (134 ± 44. 1 tmol/L). Evaluation of the area under the plasma concentration-time curve

J Filer,

to LD Stegink, Hospital

August 7, 1989. for publication October

Nutrition

from the General

Clinical

Re-

Division of Research Resources, National Inby a grant-in-aid from the NutraSweet Corn-

requests 5-385

RR59

and Pathology,

Departments

School,

University

of Pediatrics of Iowa,

Iowa

1 1, 1989.

335

Downloaded from https://academic.oup.com/ajcn/article-abstract/52/2/335/4651398 by University of Minnesota - Twin Cities user on 21 October 2018

Effect of sucrose on the metabolic disposition of aspartame13

336

STEGINK

mal adults crose.

ingesting

AFM

in beverage

with

and

without

ET

AL

suI -J

I

t

IUtItT1

I

30

U)

Subjects

and

methods

25

0

E healthy

normal

adults

(six

males,

six females)

were

1 wk before entry into the study. This screening included a physical examination, complete blood count, urinalysis, and serum analysis for concentrations of total protein, albumin, calcium, inorganic phosphorous, cholesterol, glucose, urea nitrogen, uric acid, alkaline phosphatase, lactate dehydrogenase, total bilirubin, aspartate aminotransferase, sodium, potassium, chloride, carbon dioxide, and creatinine. The proposed study was fully explained to each subject and informed, written consent was obtained. The protocol of the study was reviewed and approved by the Comstudied.

mittee

Subjects

on

were

Research

Human

Subjects

at the

Univer-

sity of Iowa.

Each subject was studied on 2 different days in the University of Iowa Clinical Research Center. On 1 study day subjects ingested 300 mL cherry-flavored beverage (Kool-Aid, General Foods Corp, White Plains, NY) providing AFM (NutraSweet Company, Deerfield, IL) at 0. 1 36 mmol/kg body wt (40 mg/ kg). On the other study day, subjects ingested 300 mL of the flavored beverage providing 0. 1 36 mmol AFM/kg body wt and 3.5 1 mmol sucrose/kg body wt (1 .2 g/kg). The order in which the two beverage servings were administered was assigned according to a balanced crossover design. An interval of 1 wk separated the 2 study days. The subjects were not allowed food after 2200 the evening before the study and were not allowed food or beverage (except water) until blood sampling was completed. Heparinized blood samples were obtained before dosing andat0.25,0.50,0.75,

1, 1.5, 2, 2.5,

3,4,6,and8

sample

ofpbasma

was

analyzed

enzymatically

for glu-

cose concentration (diagnostics procedure I 6-UV, Sigma, St Louis) and by radioimmunoassay for immunoreactive insulin (ImmoFhase Kit, Corning Medical, Medfiebd, MA; Clinical Laboratories ofthe University oflowa Hospitals & Clinics). The unsweetened cherry-flavored powdered-beverage mix and sucrose were purchased at a local grocery store. The beverage was prepared according to package instructions. Statistical analyses were done with the paired I test and analysis

of variance

Differences

were

(

17- 1 9).

considered

Data

are

significant

expressed when

15

U)

10 U)

5

-I

a.

:,,

C

,

lii

II

I

IIIt_

012345678 TIME FIG I. Plasma

adults

aspartate(ASP)concentrations(.±

administered

(APM)/kg body wt.

body

(HOURS)

beverage

wt with

(0)

providing and

without

SD)in

12 normal

0. 136 mmol (#{149}) 3.5 1 mmol

aspartame sucrose/kg

Fhe:LNAA was calculated as described by Faller(20). For the purpose ofthese calculations, prised valine, isoleucine, beucine, methionine, tyrosine, and tryptophan. The area under the centration-time curve (AUC) for each amino lated as the sum ofthe trapezoidal areas between at successive times. The base ofeach trapezoid h concentration for that amino acid.

Fernstrom and LNAAs comphenybalanine, 4-h plasma conacid was calcuplasma values was set as the 0-

Results

hafterbever-

age ingestion, through an indwelling butterfly needle with a heparin lock placed in an arm vein. The beverage was ingested over 15 mm. Blood samples were timed from the midpoint of the beverage-ingestion period. Blood samples were immediately centrifuged (2000 X g for 5 mm) to separate the plasma and erythrocytes. One portion of each plasma sample was immediately deproteinized by the addition ofan equal volume of an 80 g/L solution ofsulfosalicylic acid. The precipitated protein was removed by centrifugation (5000 X g for 5 mm) and the supernatant solution was diluted I : 1 with a solution contaming internal standards ( 14). Prepared plasma samples were stored at -70 #{176}C until analyzed to prevent boss of glutamine and cystine ( 15, 16). Amino acid analyses were carried out on an automated amino acid analyzer (model 6300, Beckman Instruments, Palo Alto, CA) as described earlier (14). The remaining

a.

screened,

Involving

20

as mean

p