Biological Interaction of Ascorbic Acid and Mineral Nutrients

23 Biological Interaction of Ascorbic A c i d and

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Mineral Nutrients NOEL W. SOLOMONS Department of Nutrition and Food Science, Massachusetts Institute of Technology, Cambridge, MA 02139, and Division of Human Nutrition and Biology, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala, Central America, Apartado 11-88 1

FERNANDO E . VITERI

Division of Human Nutrition and Biology, Institute of Nutrition of Central America and Panama, Guatemala City, Guatemala, Central America, Apartado 11-88

In the diet and at the tissue level, ascorbic acid can interact with mineral nutrients. In the intestine, ascorbic acid enhances the absorption of dietary iron and selenium; reduces the absorption of copper, nickel, and manganese; but apparently has little effect on zinc or cobalt. Ascorbic acid fails to affect the intestinal absorption of two toxic minerals studied, cadmium and mercury. At the tissue level, iron overload enhances the oxidative catabolism of ascorbic acid. Thus, the level of dietary vitamin C can have important nutritional consequences through a wide range of inhibitory and enhancing interactions with mineral nutrients.

The

n u t r i t i o n a l sciences h a v e

concern

recently

moved

from

a predominant

w i t h the identification a n d characterization of

deficiency

m a n i f e s t a t i o n s f o r i n d i v i d u a l n u t r i e n t s to a c o n s i d e r a t i o n of i n t e r a c t i o n s b e t w e e n a n d a m o n g n u t r i e n t s . A s c o r b i c a c i d represents a v i t a m i n t h a t undergoes numerous interactions w i t h other nutrients, specifically m i n erals; therefore, i t is i m p o r t a n t a n d a p p r o p r i a t e t o r e v i e w a n d u p d a t e this t o p i c .

T h e present state of k n o w l e d g e o n t h e i n t e r a c t i o n of a s c o r b i c

a c i d a n d m i n e r a l s of n u t r i t i o n a l i m p o r t a n c e is t h e subject of this c h a p t e r . Current address: Division of Disease Prevention and Control, Pan American Health Organization, Washington, DC 20037. 1

0065-2393/82/0200-0551$06.00/0 © 1982 American Chemical Society

Seib and Tolbert; Ascorbic Acid: Chemistry, Metabolism, and Uses Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

552

ASCORBIC

ACID

Minerals of Nutritional Importance A p p r o x i m a t e l y fifteen m i n e r a l s are c o n s i d e r e d chromium,

nutrients

cobalt, copper, iron, magnesium, manganese,

(calcium,

molybdenum,

n i c k e l , phosphorus, selenium, s i l i c o n , t i n , v a n a d i u m , a n d zinc);

of these

m i n e r a l s , those i n italics are essential to m a m m a l i a n n u t r i t i o n . M i n e r a l s , w h i c h are i m p o r t a n t for g o o d n u t r i t i o n , are s u p p l i e d i n a n

organism's


diet. H o w e v e r , w e h a v e r e c e n t l y r e a l i z e d t h a t the b i o l o g i c a l a v a i l a b i l i t y of the m i n e r a l s f r o m t h e i r f o o d sources is also i m p o r t a n t i n n u t r i t i o n ( J ) . I n t e r n a l m e t a b o l i s m , d i s t r i b u t i o n , a n d r e t e n t i o n are less i m p o r t a n t factors in mineral nutrition.

Nature and Scope of Ascorbic Acid—Mineral Interaction T h e p r i m a r y i n t e r a c t i o n of a s c o r b i c a c i d w i t h m i n e r a l s occurs i n t h e g a s t r o i n t e s t i n a l tract. S i g n i f i c a n t effects o n i n h i b i t i n g a n d e n h a n c i n g t h e u p t a k e of m i n e r a l s i n t o the m u c o s a or i n t o the b o d y h a v e b e e n mented.

V a r i o u s investigators h a v e p o s t u l a t e d a n u m b e r of

docu

mechanisms

that alone, or i n c o m b i n a t i o n , w o u l d be responsible for the specific i n t e r a c t i o n of a s c o r b i c a c i d w i t h a g i v e n m i n e r a l i n the gut (i.e., b y affecting the p H of the i n t e s t i n a l e n v i r o n m e n t , h a v i n g a n effect,

affecting

intraluminal solubility, causing

f o r m a t i o n , or affecting t r a n s m u c o s a l t r a n s p o r t ) .

antioxidant/reducing intraluminal complex

T h e effect of

ascorbic

a c i d o n i n t r a i n t e s t i n a l p H , p r o v i d i n g a m o r e a c i d i c e n v i r o n m e n t , has b e e n m e n t i o n e d ; this w o u l d b e m o s t i m p o r t a n t i n t h e absence of n o r m a l gastric acid production.

A s c o r b i c acid's a n t i o x i d a n t or r e d u c i n g effect m a y p r e

serve or p r o m o t e the r e d u c e d o x i d a t i o n state for a g i v e n m e t a l l i c i o n . D e p e n d i n g u p o n the specificity of the m u c o s a l a b s o r p t i o n

mechanism,

this r e d u c i n g effect c a n either r e d u c e or a u g m e n t u p t a k e . A s c o r b i c a c i d , t h r o u g h its effects o n p H a n d o x i d a t i o n state, or b y f o r m i n g c o m p l e x e s , m a y p r o m o t e i n t r a l u m i n a l s o l u b i l i t y of a m i n e r a l , p r e v e n t i n g its o l a t i o n , p o l y m e r i z a t i o n , p r e c i p i t a t i o n , or c o m p e t i t i v e

b i n d i n g i n the

intestine.

A s c o r b i c a c i d m a y also f o r m c o m p l e x e s w i t h m i n e r a l s a n d b e t a k e n u p i n t o the m u c o s a l c e l l as p a r t of a n a s c o r b i c a c i d - m i n e r a l chelate.

Finally,

a s c o r b i c a c i d m a y influence some of the t r a n s p o r t proteins i n i n t r a c e l l u l a r b i n d i n g systems for m i n e r a l s i n i n t e s t i n a l cells. W i t h i n the b o d y , a s c o r b i c a c i d a n d m i n e r a l s h a v e t w o a d d i t i o n a l levels of i m p o r t a n t i n t e r a c t i o n : i n the tissue storage a n d t u r n o v e r a s c o r b i c a c i d ; a n d i n the synthesis of tissues a n d organs.

The

of

apparent

decrease i n the h a l f - l i f e of a s c o r b i c a c i d i n the presence of excess i r o n is a n e x a m p l e of t h e f o r m e r i n t e r a c t i o n , whereas the s i m u l t a n e o u s p a r t i c i p a t i o n of v i t a m i n C , c a l c i u m , a n d p h o s p h o r u s i n the f o r m a t i o n of g r o w i n g b o n e is a n e x a m p l e of t h e latter.


23.

SOLOMONS AND VITERI

553

Ascorbic Acid 6- Mineral Nutrients

Ascorbic Acid—Iron Interaction T h e p o s s i b i l i t y of a n i m p o r t a n t i n t e r a c t i o n of a s c o r b i c a c i d a n d i r o n i n the h u m a n intestine w a s first suggested

i n 1940

(2).

Since t h e n ,

r e s e a r c h w i t h e x p e r i m e n t a l a n i m a l s a n d h u m a n subjects has and

extended

e l u c i d a t e d the b i o l o g y of the i n t e r a c t i o n . A n i m a l Studies.

Studies w i t h e x p e r i m e n t a l a n i m a l s h a v e

demon


strated e n h a n c e m e n t of i r o n a b s o r p t i o n i n the presence of a s c o r b i c a c i d . B r o w n a n d R o t h e r ( 3 ) f a i l e d to observe a n e n h a n c e m e n t of i r o n u p t a k e after 30 m i n w h e n 20 fxg of i r o n - 5 9 - l a b e l e d ferrous sulfate a n d 100 m g of a s c o r b i c a c i d w e r e i n j e c t e d b y s t o m a c h t u b e i n t o 200-g rats, b u t V a n C a m p e n ( 4 ) f o u n d t h a t 17.6 m g of a s c o r b i c a c i d p r o m o t e d the a b s o r p t i o n of a 100-/*g dose of i r o n - 5 9 - l a b e l e d f e r r i c c h l o r i d e g i v e n b y s t o m a c h t u b e to 6 - w e e k - o l d rats. U s i n g an isolated loop technique,

a twofold

increase i n i r o n - 5 9

u p t a k e i n rat intestine i n the presence of a s c o r b i c a c i d w a s d e m o n s t r a t e d ( 5 ) , a n d a s i m i l a r effect w a s n o t e d i n i s o l a t e d , p e r f u s e d g u t segments of m i c e (6).

U s i n g a n e v e r t e d i n t e s t i n a l sac t e c h n i q u e , e q u i v a l e n t e n h a n c e

m e n t of m u c o s a l u p t a k e of b o t h f e r r i c a n d ferrous ions i n the presence of 8 X 10" m M ascorbate c o n c e n t r a t i o n i n the buffer w a s s h o w n (7).

The

4

u p t a k e of i r o n - 5 9 b y e v e r t e d sacs of r a t intestine w a s l i n e a r t h r o u g h a 0.5-3.0 m M c o n c e n t r a t i o n of a s c o r b i c a c i d ; experiments o n i s o l a t e d intes t i n a l loops of rats also h a v e d e m o n s t r a t e d a d o s e - d e p e n d e n t e n h a n c e m e n t of i r o n a b s o r p t i o n b y a s c o r b i c a c i d t h r o u g h a n a s c o r b i c a c i d : i r o n m o l a r r a t i o of 1:1 to 4:1 ( 8 , 9 ) . The

Ascorbic A c i d and Therapeutic Doses of Iron in Humans.

p o t e n t i a l p h a r m a c e u t i c a l i m p o r t a n c e of a n e n h a n c e m e n t of i r o n a b s o r p t i o n i n the presence of a s c o r b i c a c i d s t i m u l a t e d extensive research o n the effect of a s c o r b i c a c i d o n t h e r a p e u t i c doses of i r o n . n i q u e s f o r assessing i r o n a b s o r p t i o n h a v e b e e n circulating method) weeks

iron concentration

(10-12);

after

an

T w o basic tech

used:

o r a l dose

of

the change iron

in

(ferremia

a n d the i n c o r p o r a t i o n of r a d i o i r o n i n t o r e d cells 2

f o l l o w i n g o r a l a d m i n i s t r a t i o n of

i r o n - 5 5 or i r o n - 5 9

(radioiron

m e t h o d ) ( 1 3 , 1 5 ) . A s u m m a r y of d a t a f r o m v a r i o u s studies is s h o w n i n T a b l e s I a n d II.

A d d e d a s c o r b i c a c i d , i n excess of 150 m g , s i g n i f i c a n t l y

i n c r e a s e d the a b s o r p t i o n of i r o n over the c o n t r o l s o l u t i o n . T h e d i s s e n t i n g o b s e r v a t i o n is t h a t of G r e b e et a l . (14)

major

w h o showed that w h e n

tracer i r o n was ferric chloride, ascorbic a c i d enhanced absorption b u t w h e n the tracer w a s ferrous sulfate, n o e n h a n c e m e n t

w a s seen.

The

authors q u e s t i o n e d the v a l i d i t y of u s i n g r a d i o l a b e l e d f e r r i c c h l o r i d e w i t h u n l a b e l e d ferrous sulfate. E x t e n s i v e subsequent experience has v a l i d a t e d this a p p r o a c h , h o w e v e r , so t h a t other e x p l a n a t i o n f o r the

nonenhance-

m e n t of i r o n a b s o r p t i o n w i t h the ferrous t r a c e r m u s t b e sought.


554

ASCORBIC A C I D

U s i n g a r a d i o i r o n t e c h n i q u e ( 1 5 ) , 105 m g of i r o n as ferrous s u l f a t e e m b e d d e d i n r e s i n to f o r m a t a b l e t w a s b e t t e r a b s o r b e d w h e n 500 m g of a s c o r b i c a c i d w a s i n c o r p o r a t e d i n t o t h e p r e p a r a t i o n as c o m p a r e d w i t h r e s i n - e m b e d d e d ferrous sulfate or a n a q u e o u s s o l u t i o n of ferrous sulfate. I n t h e t r e a t m e n t of i r o n d e f i c i e n c y a n e m i a , a m o r e r a p i d r e p l e t i o n o f h e m o g l o b i n w a s f o u n d w h e n 5 0 0 - 7 5 0 m g of s u p p l e m e n t a r y v i t a m i n


w a s g i v e n p r i o r to a n o r a l dose of t h e r a p e u t i c m e t a l l i c i r o n

(16).

Table I. Effects of Ascorbic A c i d on Absorption of Therapeutic Doses of Iron in Humans Using the Radioiron Method

Iron Dose" (mg of ferrous sulfate)

Dose of Ascorbic Acid (mg)

Ratio of Absorption with Ascorbic Acid/Without Ascorbic Acid"

30 30 30 30 30 60 60" 15 15 30 30 60 60 120° 120°

50 100 200 300 500 600 600 200 500 200 500 200 500 200 500

0.91 1.09 1.33 1.43 1.48 1.60 0.93 1.78 1.87 1.24 1.35 1.48 2.51 1.00 1.64

Reference (18) (18) (13) (13) (13) (W

(14)

(15) (15) (15) (15) (15) (15) (15) (15)

° F e C l tracer. ' Contains 10 me of ascorbic acid. 59FeS04 tracer. 5 9

3

c

Table II. Effects of Ascorbic A c i d on Absorption of Therapeutic Doses of Iron in Humans Using the Ferremia Method

Iron Dose (mg of ferrous sulfate)

Dose of Ascorbic Acid (mg)

Ratio of Absorption With Ascorbic Acid/Without Ascorbic Acid

300 200 200 4°

250 50 1000 500

1.66 1.00 1.41 1.44

Reference (10) (11) (11) (12)

• In children, mg/kg.


C

23.

SOLOMONS AND VITERI

555

Ascorbic Acid &• Mineral Nutrients

In Achlorhydria and Postgastrectomy.

T h e q u e s t i o n of

whether

a s c o r b i c a c i d w o u l d influence i r o n a b s o r p t i o n i n subjects w h o s e n o r m a l a c i d secretory c a p a c i t y h a d b e e n severely c o m p r o m i s e d b y a c h l o r h y d r i a o r g a s t r e c t o m y has b e e n a d d r e s s e d .

I n an experimental animal

model

( 1 7 ) , a d d i t i o n of 10 m g of a s c o r b i c a c i d to the r a d i o i r o n dose i n c r e a s e d i r o n a b s o r p t i o n i n a n e m i c g a s t r e c t o m i z e d rats b u t not i n i r o n - l o a d e d g a s t r e c t o m i z e d a n i m a l s . H u m a n patients w h o h a d u n d e r g o n e

partial


g a s t r e c t o m y a n d w h o w e r e a n e m i c at the t i m e of s t u d y a b s o r b e d

less

radioiron from a meal than comparably anemic individuals w i t h normal a c i d secretion ( 1 8 ) .

A d d i t i o n of oranges ( c o n t a i n i n g a s c o r b i c a c i d )

to

the m e a l i n c r e a s e d i r o n a b s o r t i o n . S i m i l a r l y , i r o n - d e f i c i e n t patients w i t h n o r m a l g a s t r o i n t e s t i n a l tracts a b s o r b e d i r o n - 5 9 f r o m b r e a d meals b e t t e r t h a n d i d e i t h e r p o s t g a s t r e c t o m y patients or s p o n t a n e o u s l y a c h l o r h y d r i c patients (19).

A d d i t i o n of 1 g of a s c o r b i c a c i d i n c r e a s e d i r o n a b s o r p t i o n

i n a l l g r o u p s i n this s t u d y , b u t the a d d e d a s c o r b i c a c i d h a d its greatest effect i n the patients w i t h a p p a r e n t l y n o r m a l a c i d secretion.

I n studies

w i t h 105-mg doses of ferrous sulfate or slow-release i r o n capsules, o n t h e other h a n d , a d d i t i o n of 500 m g of a s c o r b i c a c i d p o t e n t i a t e d i r o n a b s o r p t i o n to a greater extent i n a n e m i c p o s t - g a s t r e c t o m y patients t h a n i n patients w h o w e r e s i m p l y a n e m i c ( 2 0 ) . are l i m i t e d a n d the

findings

T h e n u m b e r of observations

s o m e w h a t inconsistent.

T h u s , no

simple

statement a b o u t the r o l e of a c i d secretion or the r o l e of a s c o r b i c a c i d as a n a c i d i f y i n g agent c a n b e m a d e o n t h e basis of these studies o n a c h l o r h y d r i a a n d gastrectomy. I t is w e l l

Ascorbic A c i d and Dietary Iron Absorption in Humans.

k n o w n t h a t i r o n occurs i n t w o forms i n the d i e t : as p a r t of t h e h e m e m o i e t y of m y o g l o b i n a n d h e m o g l o b i n i n r e d meats a n d b l o o d

(heme

i r o n ) ; a n d i n a n " i n o r g a n i c " f o r m i n f e r r i t i n a n d i n a l l f o r m s of p l a n t d e r i v e d foods ( n o n h e m e i r o n ) . P h y t a t e s , oxalates, carbonates, a n d i n o r g a n i c phosphates are a m o n g the d i e t a r y constituents t h a t r e d u c e b i o l o g i c a l a v a i l a b i l i t y of n o n h e m e i r o n (21,22).

the

A s c o r b i c a c i d has n o

i m p o r t a n t effect o n the i n t r a i n t e s t i n a l m e t a b o l i s m of h e m e i r o n , b u t a w i d e v a r i e t y of i n v e s t i g a t i o n s h a v e d e m o n s t r a t e d e n h a n c e m e n t of a b s o r p t i o n of n o n h e m e

i r o n f r o m d i e t a r y sources.

Using

the

intrinsically

r a d i o i r o n - l a b e l e d eggs, m u s t a r d greens, a n d s p i n a c h , t h e a b s o r p t i o n of i r o n w a s i n c r e a s e d b y s i m u l t a n e o u s c o n s u m p t i o n of 85 m g of

ascorbic

a c i d , e i t h e r as 200 m L of orange j u i c e or as c r y s t a l l i n e ascorbate

(23).

I r o n b a l a n c e studies c o n d u c t e d o n e i g h t I n d i a n subjects c o n s u m i n g t h e i r c u s t o m a r y diets s h o w e d a n i n c r e a s e d a p p a r e n t a b s o r p t i o n of i r o n after t h e i r d i e t w a s s u p p l e m e n t e d w i t h 100 m g of a s c o r b i c a c i d (24).

In

studies i n v o l v i n g extrinsic l a b e l i n g of v a r i o u s diets w i t h r a d i o i r o n , doses of a s c o r b i c a c i d r a n g i n g f r o m 50 to 1000 m g h a v e i n c r e a s e d i r o n a b s o r p t i o n f r o m m i x e d diets ( 2 5 ) , b r e a d (26),

eggs (27),

w h e a t (28),

soy


(28),

556

ASCORBIC

a n d m a i z e p o r r i d g e (28,29).

ACID

T h e i n h i b i t o r y effects of t h e t a n n i n s i n t e a

c a n b e p a r t i a l l y o v e r c o m e b y a d d i n g l a r g e a m o u n t s of a s c o r b i c ( 2 5 0 - 5 0 0 m g ) t o meals (30,31).

acid

T h e a b s o r p t i o n of f o r t i f i c a t i o n i r o n as

ferrous sulfate o r as f e r r i c p h o s p h a t e , p r o v i d e d i n a t a b l e salt v e h i c l e , is i n c r e a s e d b y a b o u t t h r e e f o l d w i t h t h e a d d i t i o n of 5 0 m g of a s c o r b i c a c i d W i t h a f e r r o u s - s u l f a t e - c o n t a i n i n g t a b l e salt m i x e d i n t o a m e a l

(32,33).

of c o o k e d r i c e , 60 m g of a s c o r b i c a c i d a d d e d d u r i n g c o o k i n g p r o d u c e d a Downloaded by CALIFORNIA INST OF TECHNOLOGY on November 1, 2017 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch023

s i m i l a r t h r e e f o l d increase i n i r o n a v a i l a b i l i t y (34). T h e u p t a k e of i r o n b y t h e h u m a n intestine is g o v e r n e d n o t o n l y b y its d i e t a r y f o r m a n d c o m p a n i o n consituents, b u t also b y t h e i r o n c o n d i t i o n of t h e i n d i v i d u a l .

I r o n - d e p l e t e d subjects a b s o r b a l l forms of i r o n

w i t h greater a v i d i t y t h a n d o i r o n - r e p l e t e i n d i v i d u a l s . I n h u m a n dietetics, therefore, t h e a s c o r b i c content of a d i e t c a n b e i n c l u d e d i n t h e e q u a t i o n for d e s c r i b i n g t h e b i o a v a i l a b i l i t y of i r o n f r o m a m i x e d d i e t ( 3 5 ) . T h e i n t e r a c t i o n of i r o n n u t r i t i o n a n d g r a d e d intakes of a s c o r b i c a c i d ( < 2 5 m g ; > 25 b u t < 75 m g ; a n d > 7 5 m g ) as a p r e d i c t i o n of i r o n a v a i l a b i l i t y f r o m a m i x e d N o r t h A m e r i c a n diet is p l o t t e d i n F i g u r e 1. Mechanistic Aspects of the Ascorbic Acid—Iron Interaction in the Intestine.

Studies of t h e m e c h a n i s m o f t h e i n t e r a c t i o n of a s c o r b i c a c i d

a n d i r o n at t h e m o l e c u l a r a n d c e l l u l a r levels h a v e y i e l d e d a v a r i e t y of theories. A n a c i d i c p H i n t h e l u m e n of t h e intestine favors t h e a b s o r p t i o n

^

low

medium AVAILABILITY

OF N O N H E M E

high IRON

Figure 1. The percent absorption of nonheme iron by individuals with iron body stores of 0 (---), 250 ( • ), 500 (— ), and 1000 ( ) mg is shown as influenced by the availability of nonheme iron in a given metal (35). Low availability represents < 25 mg of ascorbic acid, medium availability represents 25-75 mg of ascorbic acid, and high availability represents > 75 mg of ascorbic acid.


23.

Ascorbic Acid ir Mineral Nutrients

SOLOMONS A N D v i T E R i

557

of i r o n . W h e n the secretion of gastric a c i d is i n t a c t , t h e c o n t r i b u t i o n of i n g e s t e d a s c o r b i c a c i d to l u m i n a l p H is p r o b a b l y m i n o r . I n the absence of gastric a c i d , the c o n t r i b u t i o n of a s c o r b i c a c i d to i n t e s t i n a l p H m i g h t b e greater, b u t the d a t a f r o m the experiments i n h y p o c h l o r h y d r i c a n d a c h l o r h y d r i c a n i m a l s a n d subjects, d e s c r i b e d a b o v e , d o n o t a l l o w a n y firm

conclusions

r e g a r d i n g p H effects of a s c o r b i c a c i d .

The reducing

p o t e n t i a l of a s c o r b i c a c i d is i m p o r t a n t . T h e necessity t h a t i r o n b e i n t h e


d i v a l e n t ferrous state has b e e n r e l a t e d e i t h e r to F e

2 +

b e i n g the p r e f e r r e d

f o r m for t r a n s m u c o s a l u p t a k e or to its b e i n g less l i k e l y to p o l y m e r i z e or b i n d to other substances t h a n the t r i v a l e n t , f e r r i c ( F e ) f o r m .

Ascorbic

3 +

a c i d reduces f e r r i c i r o n i n foods s u c h as e g g y o l k to ferrous i r o n T h e i r o n i n e g g y o l k is present as f e r r i c h y d r o x i d e . e x p e r i m e n t s w i t h i n t r i n s i c a l l y l a b e l e d e g g y o l k (36)

(36).

I n i n vitro dialysis or i n h e m o g l o b i n

r e p l e t i o n studies i n g r o w i n g rats f e d o n e g g y o l k ( 3 7 ) , o n l y those r e d u c i n g agents t h a t also h a d a c o m p l e x i n g p o t e n t i a l c o u l d effectively

reduce

f e r r i c i r o n i n egg y o l k or e n h a n c e its i r o n a b s o r p t i o n i n t o the rat. T h u s , o - p h e n a n t h r o l i n e , a n i r o n c o m p l e x i n g agent w i t h o u t r e d u c i n g p o t e n t i a l , a n d s o d i u m sulfite, a - t o c o p h e r o l , or h y d r o q u i n o n e , r e d u c i n g agents w i t h out complexing

potential, showed

n o effect i n these

egg-yolk-related

e x p e r i m e n t s . A s c o r b i c a c i d has b o t h r e d u c i n g a n d c o m p l e x i n g p o t e n t i a l . I n vitro experiments

(38)

showed

that iron c o u l d form

soluble

chelates w i t h a s c o r b i c a c i d at the p H of the n o r m a l i n t e s t i n a l l u m e n . S o l u b l e a s c o r b i c acid—iron chelates f o r m e d at a n a c i d i c p H r e m a i n e d i n s o l u t i o n e v e n after the a l k a l i n i z a t i o n of the m e d i u m ( 3 9 ) . I n t r a i n t e s t i n a l i n s t a l l a t i o n of the p H - a d j u s t e d chelates i n t o the rat e n h a n c e d the a b s o r p t i o n of i r o n .

T h e authors also suggest that the a s c o r b i c a c i d n o r m a l l y

present i n m a m m a l i a n b i l e has a p h y s i o l o g i c a l l y i m p o r t a n t role i n t h e a b s o r p t i o n of n o n h e m e i r o n f r o m the diet. W h e t h e r the w h o l e

ascorbic

a c i d - i r o n chelate is t a k e n u p i n t a c t i n t o the m u c o s a l c e l l u n d e r these c o n d i t i o n s has not b e e n e s t a b l i s h e d .

I r o n is, at the same t i m e ,

s o l u b l e , r e d u c e d , a n d m o r e a b s o r b a b l e at i n t e s t i n a l p H i n the

more

presence

of a s c o r b i c a c i d ; those factors, w i t h or w i t h o u t d i r e c t m u c o s a l u p t a k e of a s c o r b i c acid—iron complexes,

e x p l a i n the c o n t r i b u t i o n of a s c o r b i c

acid

to the e n h a n c e m e n t of i r o n a v a i l a b i l i t y . Effects of Excess Tissue Iron on Ascorbic A c i d Metabolism.

Epi

d e m i o l o g i c a l observations a m o n g the B a n t u of S o u t h A f r i c a s h o w e d a n a p p a r e n t association of c l i n i c a l s c u r v y i n a d u l t males w i t h hemosiderosis common

to this g r o u p .

B o t h plasma clearance

of

ascorbic

acid

and

u r i n a r y e x c r e t i o n of a s c o r b i c a c i d w e r e a l t e r e d i n severe i r o n o v e r l o a d ; plasma clearance was increased a n d urinary excretion was decreased i n s i d e r o t i c subjects

(40,41).

T h e e v i d e n c e w a s i n t e r p r e t e d as a d e m o n

s t r a t i o n of e n h a n c e d o x i d a t i v e c a t a b o l i s m of a s c o r b i c a c i d i n the presence of excess tissue i r o n .


558

ASCORBIC

ACID

Ascorbic Acid—Cobalt Interaction C o b a l t has n o c o n f i r m e d n u t r i t i o n a l r o l e i n m a m m a l i a n o r g a n i s m s a s i d e f r o m its p a r t i c i p a t i o n i n t h e c o r r i n r i n g s t r u c t u r e of c o b a l a m i n s ( v i t a m i n B i ) . N o n e t h e l e s s , i n o r g a n i c c o b a l t is a b s o r b e d b y t h e intes 2

tine. T h a t this a b s o r p t i o n p a t h w a y w a s s h a r e d w i t h i r o n w a s first s u g gested b y t h e o b s e r v a t i o n of a m i n e r a l - m i n e r a l c o m p e t i t i o n (42). T h e


use of radioisotopes of i r o n i n d i a g n o s t i c tests of a b s o r p t i o n f o r c h a r a c t e r i z i n g i r o n n u t r i t i o n i n h u m a n subjects has b e e n a d v a n c e d

(43-45).

A n excellent c o r r e l a t i o n b e t w e e n a b s o r p t i o n of r a d i o i r o n a n d r a d i o c o b a l t has b e e n r e p o r t e d

(43-45).

I n a series of studies c o n d u c t e d o n h u m a n v o l u n t e e r s i n t h e D i v i s i o n of H u m a n N u t r i t i o n a n d B i o l o g y at t h e I n s t i t u t e of N u t r i t i o n of C e n t r a l A m e r i c a a n d P a n a m a , w e e m p l o y e d t h e r a d i o c o b a l t a b s o r p t i o n test i n t h e context of i r o n a b s o r p t i o n tests.

W e u s e d a m o d i f i c a t i o n of a 6 - h

c o b a l t e x c r e t i o n test t o estimate a b s o r p t i o n (44). A p p r o x i m a t e l y 2.5 / x C i of c o b a l t - 6 0 m i x e d w i t h 4.74 m g ( 2 0 /xmol) of c o b a l t c h l o r i d e h e x a h y d r a t e w a s g i v e n i n 100 m L of w a t e r after a n o v e r n i g h t fast. T h e subjects remained fasting for 2 h postingestion a n d then consumed a standard breakfast. A l i t e r o r m o r e of w a t e r w a s c o n s u m e d d u r i n g t h e final 4 h o f the s t u d y . A l l u r i n e p r o d u c e d d u r i n g t h e 6 h w a s c o l l e c t e d ; t h e e x c r e t e d radioactivity was measured i n a well-type y-counter. I n a g r o u p of t e n u r b a n , n o n a n e m i c a d u l t s a n d i n n i n e t e e n r u r a l a g r i c u l t u r a l w o r k e r s w i t h v a r y i n g degrees of i r o n deficiency, a p a i r of c o b a l t a b s o r p t i o n tests w a s p e r f o r m e d .

O n one occasion, the cobalt-60

dose

w a s g i v e n a l o n e ; o n t h e other occasion, 1000 m g of a s c o r b i c a c i d w a s a d d e d t o t h e c o b a l t - 6 0 dose. T a b l e I I I shows t h e d a t a o n t h e t e n n o r m a l Table III. Comparison of the 6-h Excretion of Cobalt-60 Administered Alone or with 1000 mg of Ascorbic A c i d in N o r m a l Subjects Percent Without

mean se

of Oral Dose Excreted

Ascorbic

Acid

in the

With Ascorbic

18.9 11.5 22.2 7.6 15.0 18.9 19.0 7.5 22.6 8.7

17.8 12.5 24.7 9.9 11.0 14.8 13.2 13.6 27.6 14.3

13.2 ±6.5

15.9 ± 5.8

When

Urine

Acid


A 1.1 •1.0 2.5 2.3 4.0 4.1 5.8 6.1 5.0 5.6

23.

SOLOMONS

subjects.

A N D

559

Ascorbic Acid I? Mineral Nutrients

VITERI

N o differences of statistical significance w e r e n o t e d b y p a i r e d

S t u d e n t f-test a n a l y s i s , as w a s t r u e w h e n d a t a f r o m a l l t w e n t y - n i n e s u b jects w e r e g r o u p e d .

T h e e x c r e t i o n of r a d i o i s o t o p i c c o b a l t i n 6 h as a

p e r c e n t a g e of the a d m i n i s t e r e d dose w a s 26.5 ± a n d 23.8 ±

13.0% w i t h cobalt alone

12.7% w i t h cobalt plus ascorbic a c i d (mean ±

sd).

Linear

regression of the p a i r e d d a t a r e v e a l e d a c o r r e l a t i o n coefficient

of r =

0.768 ( p < 0.001). A p p a r e n t l y , i n aqueous s o l u t i o n , a s c o r b i c a c i d has n o Downloaded by CALIFORNIA INST OF TECHNOLOGY on November 1, 2017 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch023

e f f e c t — i n h i b i t i n g or e n h a n c i n g — o n the a b s o r p t i o n of r a d i o c o b a l t .

This

is i n contrast to the experience of w o r k e r s u s i n g ferrous i r o n i n s o l u t i o n , d i s c u s s e d e a r l i e r . W e also h a v e d e m o n s t r a t e d a t w e l v e f o l d decrease i n c o b a l t e x c r e t i o n w h e n the dose w a s m i x e d i n t o a m e a l (46),

but whether

or not s i m u l t a n e o u s a d m i n i s t r a t i o n of a s c o r b i c a c i d w o u l d alter c o b a l t a b s o r p t i o n i n the presence of f o o d has not b e e n e x a m i n e d .

Ascorbic Acid—Copper Interaction I n h i b i t i o n of

intestinal copper

absorption by

ascorbic

acid

was

o b s e r v e d i n e x p e r i m e n t a l a n i m a l s . A d d i n g 5 g of a s c o r b i c a c i d / k g of poultry ration containing 8 m g

of

copper

exacerbated

copper

defi

c i e n c y signs i n c l u d i n g g r o w t h r e t a r d a t i o n , a n e m i a , a n d m o r t a l i t y f r o m a o r t i c r u p t u r e i n c h i c k s (47).

A o r t i c rupture was caused b y

defective

elastin formation, a copper-dependent function. T h e time to appearance of a o r t i c r u p t u r e w a s also d e c r e a s e d b y the 0 . 5 %

ascorbic-acid-contain

i n g diet. E v e n w i t h a c o p p e r content of 24 m g / k g , 0 . 5 % a s c o r b i c a c i d produced anemia. G r o w t h reduction a n d anemia was observed (47) D u t c h r a b b i t s o n a d i e t c o n t a i n i n g 3 p p m of c o p p e r b y a d d i n g

in

1.0%

a s c o r b i c a c i d , a l t h o u g h n o signs of c o p p e r deficiency w e r e e v i d e n t w i t h the 3-ppm

copper

r a t i o n alone

(48)

(Table I V ) .

A d d i t i o n of

0.1%

a s c o r b i c a c i d to a c o p p e r - d e f i c i e n t diet f e d to c h i c k s d e c r e a s e d g r o w t h , i n c r e a s e d m o r t a l i t y , a n d r e d u c e d a o r t i c e l a s t i n content ( 4 9 ) . i d e n t i c a l results w e r e o b t a i n e d w i t h t u r k e y p o u l t s ( 5 0 ) .

Essentially

I n guinea pigs

Table IV. Effects of Ascorbic A c i d on Symptoms of Copper Deficiency in D u t c h Rabbits Fed Low-Copper Diets Weight (%) C u ( 2 p p m ) , A A (0%) C u ( 3 p p m ) , A A (0%) C u (3 p p m ) , A A ( 1 % )

6wk 68 96 81

12 wk 47 94 62

Hemoglobin 18 wk 39 — 61

6 wk 75 107 66

12 wk 59 93 73

(%) 18 wk 71 — 88

Note: Data are expressed as a percentage of value for animals consuming a con trol diet containing 6 ppm Cu. A A = ascorbic acid. Source: Reference 48.


560

ASCORBIC

ACID

f e d a r a t i o n c o n t a i n i n g 21 p p m of c o p p e r , a d j u s t i n g the d i e t a r y a s c o r b i c a c i d c o n t e n t to 1.0%

caused a 3 9 % reduction i n whole blood

copper

c o n c e n t r a t i o n a n d a 5 2 % r e d u c t i o n i n l i v e r c o p p e r c o n t e n t as c o m p a r e d w i t h animals receiving a standard diet w i t h 0 . 1 % A d d i t i o n of 2 . 5 %

ascorbic a c i d

(51).

a s c o r b i c a c i d to the diets of m i n i p i g s c o n s u m i n g a n

adequate copper intake produced only slight retardation i n weight gain ( 5 2 ) ; w h e n the a n i m a l s w e r e p l a c e d o n a c o p p e r - d e f i c i e n t diet, a s c o r b i c Downloaded by CALIFORNIA INST OF TECHNOLOGY on November 1, 2017 | http://pubs.acs.org Publication Date: June 1, 1982 | doi: 10.1021/ba-1982-0200.ch023

a c i d provoked a sharper fall i n weight a n d earlier death.

Hepatic and

s e r u m c o p p e r levels w e r e l o w e r i n the a s c o r b i c - a c i d - s u p p l e m e n t e d mals

ani

(52). I n y o u n g s w i n e , a d d i t i o n of 0 . 5 % a s c o r b i c a c i d to a d i e t c o n t a i n i n g

a toxic a m o u n t of c o p p e r , 250 m g / k g of diet, r e d u c e d the a n e m i a t h a t w a s the toxic m a n i f e s t a t i o n of c o p p e r excess, a n d r e d u c e d h e p a t i c a c c u m u l a t i o n of c o p p e r

(53).

A b s o r p t i o n of a t r a c e r dose of c o p p e r - 6 4 f r o m i n s i t u l i g a t e d seg ments of rat intestine i n 250 -350-g a n i m a l s w a s r e d u c e d b y t h e s i m u l taneous a d m i n i s t r a t i o n of 2.5 m g of a s c o r b i c a c i d (54). Radiocopper a b s o r p t i o n w a s also r e d u c e d i n c h i c k s r e c e i v i n g a 0 . 1 % a s c o r b i c a c i d ration (55). L

T h e m e c h a n i s m of this effect is not k n o w n . H i l l a n d S t a r c h e r p o s t u l a t e d t h a t r e d u c t i o n of c o p p e r f r o m its d i v a l e n t ( c u p r i c ) its m o n o v a l e n t ( c u p r o u s )

(49)

state t o

state a c c o u n t e d for the i m p a i r e d a b s o r p t i o n

of c o p p e r i n the presence of a s c o r b i c a c i d ; t h e y p r o d u c e d the same effect w i t h a n o t h e r r e d u c i n g agent, d i m e r c a p t o p r o p a n o l ( B A L ) .

This explana

t i o n has b e e n a c c e p t e d b y others ( 5 6 ) , a l t h o u g h the o x i d a t i o n state of c o p p e r for m a x i m u m i n t e s t i n a l a b s o r p t i o n has not b e e n e s t a b l i s h e d . A n i n t r a m u c o s a l c o m p e t i t i o n of a s c o r b i c a c i d for s u l f h y d r y l sites o n m e t a l l o t h i o n e i n s was d e m o n s t r a t e d ( 5 7 ) .

I f this l i g a n d has a n y r e g u l a t o r y r o l e

i n c o p p e r u p t a k e , this a l t e r n a t i v e m e c h a n i s m of a s c o r b i c

acid-copper

i n t e r a c t i o n c o u l d e x p l a i n the m e c h a n i s m . E x p e r i m e n t a l c o n f i r m a t i o n of a n a s c o r b i c - a c i d - i n d u c e d i n h i b i t i o n of c o p p e r a b s o r p t i o n i n the h u m a n intestine has not b e e n p r e s e n t e d .

Ascorbic Acid—Zinc Interaction G i v e n t h e effects of a s c o r b i c a c i d o n the a b s o r p t i o n of i r o n a n d c o p p e r , investigators h a v e b e e n i n t e r e s t e d i n p o s s i b l y significant i n t e r actions w i t h z i n c .

T h e a b s o r p t i o n of z i n c a n d other d i v a l e n t m i n e r a l

ions w a s s t u d i e d u s i n g a n i s o l a t e d , filled d u o d e n a l l o o p i n s i t u i n t h e rat (58).

A 1 0 " - M z i n c s o l u t i o n w a s i n f u s e d i n the presence or absence 4

of 10" M ascorbate or d e h y d r o a s c o r b a t e . 2

A two-thirds reduction i n the


23.

561

Ascorbic Acid ir Mineral Nutrients

SOLOMONS AND VITERI

net a b s o r p t i o n of z i n c f r o m the l u m e n was o b s e r v e d d u r i n g a 5-h e x p e r i ment.

Over 90%

of the z i n c t a k e n u p i n t h e aqueous s o l u t i o n

alone

r e m a i n e d i n the m u c o s a l cells; h o w e v e r , over 5 0 % of the z i n c a b s o r b e d i n the presence of a 100-fold m o l a r excess of a s c o r b i c a c i d or

dehydro

a s c o r b i c a c i d was t r a n s f e r r e d to the b o d y . T h u s , the net a m o u n t of z i n c r e a c h i n g the i n t e r n a l organs of the rat i n 5 h was f o u r to six times greater w i t h ascorbate or

dehydroascorbate.


W e h a v e c o n d u c t e d i n v i v o experiments o n the i n t e r a c t i o n of a n d a s c o r b i c a c i d i n the h u m a n intestine ( 5 6 ) .

zinc

T o assess a b s o r p t i o n

we

m o n i t o r e d the p l a s m a z i n c c o n c e n t r a t i o n after a n o r a l dose of 25 m g of e l e m e n t a l z i n c as z i n c sulfate i n 100 m L of w a t e r t a k e n i n the f a s t i n g state. T h e p l a s m a z i n c l e v e l was m e a s u r e d p r i o r to z i n c a d m i n i s t r a t i o n a n d at h o u r l y i n t e r v a l s thereafter for 4 h . T h e a d d i t i o n of g r a d e d doses of 0.5, 1.0, a n d 2.0 g of a s c o r b i c a c i d , c o n s t i t u t i n g Z n : A A m o l a r ratios of 0.134, 0.067, a n d 0.034, r e s p e c t i v e l y , to the 2 5 - m g s o l u t i o n of z i n c h a d n o effect o n the v e l o c i t y of z i n c a b s o r p t i o n

(Figure 2).

However,

be

cause t h e effect of a s c o r b i c a c i d i n i m p r o v i n g n o n h e m e i r o n a b s o r p t i o n w a s most d r a m a t i c a l l y seen i n the presence of f o o d or beverages, f u r t h e r studies w e r e c o n d u c t e d i n w h i c h the c h a n g e i n p l a s m a z i n c

following

the i n g e s t i o n of 108 m g of z i n c as z i n c sulfate m i x e d w i t h 120 g of b l a c k b e a n g r u e l , a k n o w n i n h i b i t o r of z i n c a b s o r p t i o n (59, 60) w a s m e a s u r e d . Studies w e r e c o n d u c t e d b o t h i n the presence a n d absence of 2 g ascorbic acid ( F i g u r e 3 ) .

O n c e a g a i n , no effect of a d d e d ascorbic

of

acid

w a s d e t e c t e d . A t least for h u m a n s , there appears to b e n e i t h e r a n i n h i b i t i n g n o r a n e n h a n c i n g influence of a s c o r b i c a c i d o n t h e b i o l o g i c a l a v a i l a b i l i t y of o r a l l y i n g e s t e d z i n c . Zinc and Ascorbic A c i d Metabolism

and Excretion.

I r o n has a n

o x i d i z i n g effect o n a s c o r b i c a c i d , r e d u c i n g its u r i n a r y e x c r e t i o n ; fore, K e l t z et a l . (61)

questioned

there

whether zinc w o u l d show a similar

effect. H u m a n subjects w e r e f e d a d i e t c o n t a i n i n g either 11.5 or 19.5 m g of z i n c / d for 7-d b a l a n c e p e r i o d s . D a i l y a s c o r b i c a c i d i n t a k e was 100 m g . C o n s i s t e n t w i t h the

findings

f r o m i r o n - l o a d e d A f r i c a n s , the h i g h e r z i n c

i n t a k e c a u s e d a significant 3 0 % decrease i n u r i n a r y ascorbate excretion. N o e x p l a n a t i o n for the z i n c - r e l a t e d r e d u c t i o n i n ascorbic a c i d b e y o n d t h e a n a l o g y w i t h the i r o n - l o a d e d i n d i v i d u a l s is r e a d i l y a v a i l a b l e . In

a study

w i t h experimental

animals

(62),

both

ascorbic

acid

(2.5 m M / k g d o s e ) a n d z i n c as z i n c sulfate (1.4 m M / k g d o s e ) i n c r e a s e d e t h a n o l clearance f r o m the b l o o d of i n t o x i c a t e d , 250-g rats w h e n sterile solutions of the respective T h e effects a p p e a r e d

compounds were injected

to b e i n d e p e n d e n t ,

intraperitoneally.

because neither additive

nor

s y n e r g i s t i c effects o n clearance w e r e n o t e d w h e n the t w o agents w e r e injected

simultaneously.



HOURS AFTER DOSE 2

Figure 2. The change in plasma zinc concentration (mean ± se) at 60-min intervals for 4 h after various graded doses of ascorbic acid mixed with 110 mg of ZnSO^ • 7H 0 (56). Key: 0 0 , 0.5 g of ascorbic acid; V — • — V , 1.0 g of ascorbic acid; and O O , 2.0 g of ascorbic acid. Five subjects participated in each experiment. The heavy line shows the curve of zinc sulfate alone (Figure 1). No significant differences are found among any of the hourly points.

100 - i



z

±

Figure 3. The change in plasma zinc concentration (mean se) over 4 h for five subjects consuming 475 mg of ZnSO^ • 7H O (containing 108 mg of zinc) mixed into 120 g of black bean gruel (56). The mean was consumed either alone (• or with 2.0 g of ascorbic acid (M — • — M), by five subjects. No significant differences are observed.

60


^ oo

564

ASCORBIC

ACID

Ascorbic Acid—Nickel Interaction The

essentiality of

n i c k e l i n v a r i o u s h i g h e r forms

of

mammals,

i n c l u d i n g rats, goats, sheep, a n d p i g s , has b e e n d e m o n s t r a t e d N i c k e l is also h o m e o s t a t i c a l l y r e g u l a t e d i n h u m a n s (66).

(63-66).

B a l a n c e studies

suggested t h a t the a b s o r p t i o n of n i c k e l f r o m n o r m a l A m e r i c a n meals is o n t h e o r d e r of 1 0 %

(68).

V i r t u a l l y n o t h i n g is k n o w n , h o w e v e r ,

about


t h e factors affecting the b i o a v a i l a b i l i t y of n i c k e l i n h u m a n s . A d e t e c t a b l e rise i n p l a s m a n i c k e l c o n c e n t r a t i o n after the o r a l a d m i n i s t r a t i o n of 22.4 m g of n i c k e l sulfate w a s r e p o r t e d (69).

I n collaborative

s t u d i e s , w e h a v e e x a m i n e d the i n t e r a c t i o n of n i c k e l a n d a s c o r b i c a c i d 2

i n the h u m a n intestine. H e a l t h y volunteers r e c e i v e d 5 m g of e l e m e n t a l n i c k e l as 22.4 m g of n i c k e l sulfate, as i n the p r e v i o u s report. T h e t o t a l v o l u m e w a s 100 m L .

T h i s w a s i n g e s t e d either a l o n e or w i t h 1 g

a s c o r b i c a c i d . T h i s c o n s t i t u t e d a N i : A A m o l a r r a t i o of 0.015.

of

A signifi

c a n t d e p r e s s i o n i n the rise of p l a s m a n i c k e l w a s o b s e r v e d w h e n a s c o r b i c a c i d w a s present as c o m p a r e d w i t h the s i t u a t i o n of aqueous n i c k e l a l o n e (see T a b l e V ) .

O u r N i : A A r a t i o of 0.015 c o m p a r e s w i t h a m o l a r r a t i o

Table V . Effect of Ascorbic A c i d (1 g) on the Absorption of N i c k e l (5 mg) as N i c k e l Sulfate in H u m a n Subjects Change in Plasma Nickel Above Fasting Levels (fig/mL) 1 h

Sh

2h

4h

N i c k e l alone

48.8 ±12.6

73.0 ±11.1

80.0 ±11.3

53.3 ±16.3

Nickel with A A

29.9 ±10.3

38.6 ±4.8

52.8 ±4.5

42.3 ±6.3

Significance

N.S.

p

Biological Interaction of Ascorbic Acid and Mineral Nutrients

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