16 Kinetics of Ascorbic A c i d in Humans A. KALLNER, D. HARTMANN, and D. HORNIG 1
2
Karolinska Institutet, Department of C l i n i c a l Chemistry, S-104 01 Stockholm, Sweden
Kinetic parameters were estimated in nonsmokers and smokers to help elucidate the quantitative ascorbate me tabolism in humans. This approach allows calculation of turnover rates at different levels of steady state intakes of ascorbate. Metabolic and renal turnovers were calculated separately. At plasma levels above about 0.7 mg/100 mL the renal elimination increased sharply and the metabolic turnover showed a saturation at a plasma level correspond ing to a total turnover of about 60 mg/d. At the tested levels of intake of ascorbic acid the calculated total pool size increased to a level reached at a steady state plasma concentration achieved at an intake of about 90 mg/d. At intakes of this magnitude the absorption is substantially less than 100%. A daily intake of 100 mg of ascorbate for larger populations should be attained. Similar experiments with smokers showed an increase in the metabolic turnover corresponding to a demand of 140 mg/d to reach a similar stage.
Scurvy is the ultimate result of ascorbic acid deficiency. Untreated, this disease leads to a painful death with a multitude of symptoms, such as weakness, profuse bleeding from mucous membranes and infec tions, loss of teeth, and symptoms from joints and ligaments. In modern communities this condition should not be seen and even mild scurvy should be extremely rare. During recent years it has been questioned if ascorbate in very high doses might be beneficial to humans. Today, it is 1
Current address: Biological Pharmaceutical Research Department, F. Hoff mann-La Roche & Co., Ltd, CH-4002, Basle, Switzerland. Current address: Department of Vitamin & Nutrition Research, F. HoffmannLa Roche Co., Ltd, CH-4002, Basle, Switzerland. 2
0065-2293 /82/0200-0335$06.00/ 0 © 1982 American Chemical Society
336
ASCORBIC
r e l e v a n t to discuss o p t i m a l i n s t e a d of m i n i m a l intakes.
The
ACID
apparent
n o n t o x i c i t y of ascorbate makes i t e t h i c a l l y a n d p h y s i o l o g i c a l l y a c c e p t a b l e to a r g u e for m e g a d o s e intakes of this c o m p o u n d , a l t h o u g h the benefits thereof m a y n o t yet b e
finally
settled.
F o r several years the r e c o m m e n d e d
dietary allowance
(RDA)
of
v i t a m i n C has v a r i e d f r o m c o u n t r y to c o u n t r y . I t w a s r e c e n t l y i n c r e a s e d f r o m 45 to 60 m g / d i n the U n i t e d States ( J ) .
Probably, healthy people
i n t h e i r a c t i v e ages n o r m a l l y ingest this a n d even l a r g e r a m o u n t s t h r o u g h t h e i r d i e t a r y h a b i t s , whereas e l d e r l y p e o p l e , diseased p e o p l e , or p e o p l e u n d e r s p e c i a l c i r c u m s t a n c e s l i k e a l c o h o l i c s m a y b e at a n a c t u a l risk a n d n e e d s u p p l e m e n t a t i o n to m e e t the b a s a l needs for the v i t a m i n . T r a n s f e r r i n g results of studies of the m e t a b o l i c r o l e a n d fate of ascor b a t e i n a n i m a l experiments to h u m a n s is l i m i t e d b e c a u s e most a n i m a l s are a b l e to synthesize t h e i r n e e d of ascorbate e n d o g e n o u s l y a n d i n those a n i m a l s w h e r e ascorbate is a v i t a m i n (e.g., the g u i n e a p i g ) , the m e t a b o l i s m of ascorbate
differs f r o m t h a t i n h u m a n s .
E s t i m a t i o n of
human
needs w i l l therefore h a v e to b e d e r i v e d f r o m e x p e r i m e n t s w i t h h u m a n s .
Early
Accounts
of
Scurvy
A large d o c u m e n t a t i o n o n s c u r v y has b e e n a c c u m u l a t e d d u r i n g t h e centuries.
S o m e r e l e v a n t reports, w h i c h c o n t a i n k i n e t i c i n f o r m a t i o n o n
the d e v e l o p m e n t of ascorbate deficiency, w i l l b e r e v i e w e d b r i e f l y . first w e l l - k n o w n , d e t a i l e d , a n d c o m p r e h e n s i v e
The
r e p o r t o n this disease,
" T r e a t i s e o n S c u r v y , " w a s p u b l i s h e d i n 1757 b y the S c o t t i s h n a v a l p h y s i c i a n James L i n d ( 2 ) .
S o m e case reports are c i t e d here.
Thus, during
t h e j o u r n e y of H . M . S . Salisbury f r o m A u g u s t 10 to O c t o b e r 28, 1746 (i.e., 75 d ) , o n l y one s a i l o r w a s r e p o r t e d i l l w i t h the disease.
I n a r e p o r t of
f o u r ships b o u n d for the E a s t I n d i e s , 105 out of 424 sailors w e r e r e p o r t e d d e a d f r o m s c u r v y w i t h i n 4 m o n t h s . O t h e r f r a g m e n t a r y notes are official reports b y the D a n i s h a n d D u t c h E a s t I n d i a C o m p a n i e s of r e g u l a r o u t breaks of the disease after 5 - 6 m o n t h s at sea. T h i s w a s i n the seventeenth century. A n o t h e r i n t e r e s t i n g source of i n f o r m a t i o n is t h e f a m o u s r e p o r t f r o m the D a n i s h d i c o v e r e r Jens M u n k w h o h a d to stay the w i n t e r i n H u d s o n B a y i n the 1620s.
I n 9 m o n t h s a l l b u t 3 out of a b o u t 400 sailors d i e d ,
m a i n l y f r o m s c u r v y . E v e r y case w a s r e p o r t e d b y the c a p t a i n ( w h o
was
a m o n g those s u r v i v i n g ) a n d the first case a p p e a r e d a r o u n d C h r i s t m a s or a b o u t 3 m o n t h s after t h e ships h a d b e e n c a u g h t b y t h e ice. T h i s i n f o r m a t i o n i n d i c a t e s t h a t d e p l e t i o n of t h e ascorbate p o o l s t o a l e v e l c a u s i n g s c u r v y takes 2 - 4 m o n t h s , b u t some p e o p l e m a y s u r v i v e
16.
KALLNER
longer.
ET
337
Kinetics of Ascorbic Acid
AL.
I n retrospect one m a y assume t h a t the s u r v i v o r s h a d access to
a d d i t i o n a l d i e t a r y sources.
Ascorbic
Acid Kinetics
in
Humans
E x p e r i m e n t a l a p p r o a c h e s to h u m a n r e q u i r e m e n t s of ascorbate c a n b e m a d e u s i n g k i n e t i c m e t h o d s ; the most o b v i o u s m e t h o d is to p e r f o r m d e p l e t i o n a n d r e p l e t i o n studies.
E x p e r i m e n t a t i o n w i t h d e p l e t i o n of
a
n u t r i e n t i n h u m a n beings is difficult, b u t o u r f u n d a m e n t a l k n o w l e d g e a b o u t ascorbate
k i n e t i c s i n h u m a n s has b e e n a c h i e v e d t h r o u g h s u c h
studies. I n the late 1960s a n d e a r l y 1970s B a k e r a n d c o w o r k e r s ( 3 - 5 ) that a n almost c o m p l e t e
p a r t i c i p a t i n g subjects o c c u r r e d i n 1 0 0 - 1 3 0 symptoms
found
d e p l e t i o n of the ascorbate pools of t h e i r six
of s c u r v y also o c c u r r e d .
d.
A t this t i m e , signs a n d
T h e decrease
of ascorbate
pools
f o l l o w e d a n e x p o n e n t i a l p a t h a n d s h o w e d a r e l a t i v e decrease of
about
3 % / d , c o r r e s p o n d i n g to a h a l f - l i f e of a b o u t 60 d . T h e signs a n d s y m p toms of s c u r v y o c c u r r e d at a b o d y p o o l of a b o u t 300 m g of
ascorbate.
O n r e p l e t i o n , i n g e s t e d ascorbate w a s e x c r e t e d i n u r i n e w h e n the p o o l h a d r e a c h e d a b o u t 1500 m g . i n t a k e of 45 m g ( 3 %
B a k e r a n d his g r o u p stated t h a t a d a i l y
of 1500 m g ) w o u l d m a i n t a i n this p o o l size. T h i s
a m o u n t also b e c a m e the official R D A i n the U n i t e d States for s e v e r a l years. R e t r o s p e c t i v e l y , the c a l c u l a t i o n s w e r e m a d e o n observations d u r i n g a d e p l e t e d stage, therefore the r e l a t i v e decrease of the ascorbate p o o l i n c o m p a r i s o n w i t h a n o r m a l ascorbate status m a y h a v e b e e n u n d e r e s t i m a t e d . I n agreement w i t h this u n d e r e s t i m a t i o n , the h a l f - l i f e w o u l d h a v e b e e n o v e r e s t i m a t e d a n d the m i n i m u m dosage to r e t a i n b a l a n c e conse quently w o u l d have been underestimated. A l t e r n a t i v e l y , studies b a s e d o n steady state k i n e t i c s of p h y s i o l o g i c a l intakes c a n b e p e r f o r m e d .
S u c h studies r e q u i r e t h a t the subject
be
e q u i l i b r a t e d o n a c e r t a i n l e v e l of i n t a k e of t h e c o m p o u n d to b e s t u d i e d . A f t e r e q u i l i b r a t i o n , a r a d i o a c t i v e t r a c e r dose of the c o m p o u n d
under
c o n s i d e r a t i o n is g i v e n . T h e d i s t r i b u t i o n of the l a b e l e d c o m p o u n d i n t h e b o d y is s t u d i e d as w e l l as its e l i m i n a t i o n . T h u s v o l u n t e e r s c a n b e s u b j e c t e d to intakes of v a r i o u s m a g n i t u d e s , a n d i n our study (6) healthy, male, nonsmoking volunteers were e q u i l i b r a t e d o n f o u r different levels of intakes of ascorbate. T h e levels s t u d i e d w e r e 30, 60, 90, a n d 180 m g / d . T h e s e a m o u n t s are b e l o w , at, a n d a b o v e the p r e s e n t l y r e c o m m e n d e d dosages, b u t a l l m a y b e r e g a r d e d as p h y s i o l o g i c a l i n the sense that the m a i n p a r t of the p o p u l a t i o n p r o b a b l y has intakes of these m a g n i t u d e s . T h e experiments w e r e e n d e d 2 w e e k s after
338
ASCORBIC
a d m i n i s t r a t i o n of t h e
1 4
ACID
C - l a b e l e d ascorbate b y g i v i n g l a r g e doses ( 2 - 4
X
500 m g ) of ascorbate to " w a s h o u t " the l a b e l . T h i s w a s h o u t prevents a n unnecessary exposure to r a d i o a c t i v i t y a n d i m p r o v e s the a c c u r a c y of the estimation of the a b s o r b e d a m o u n t of r a d i o a c t i v i t y . T h e k i n e t i c a p p r o a c h r e q u i r e s c h o o s i n g a m a t h e m a t i c a l m o d e l that c a n b e fitted to the e x p e r i m e n t a l d a t a . A p r o p e r l y c h o s e n m o d e l w i l l a l l o w c a l c u l a t i o n of t u r n o v e r of m e t a b o l i c a n d e x c r e t i o n a l pools. ther, one c a n c a l c u l a t e the v a r i o u s p o o l sizes.
Fur
H o w e v e r , the m o d e l is
n o t h i n g b u t a m o d e l a n d does not necessarily h a v e a n y r e s e m b l a n c e to p h y s i o l o g i c a l or m e d i c a l c i r c u m s t a n c e s . T h e d e c a y p a t t e r n of p l a s m a r a d i o a c t i v i t y ( F i g u r e 1) i n d i c a t e d t h a t a t h r e e - c o m p a r t m e n t m o d e l c o u l d be chosen for c a l c u l a t i o n of the k i n e t i c data.
T h e chosen m o d e l consists of a c e n t r a l c o m p a r t m e n t ( F i g u r e 2 )
i n t o w h i c h d i e t a r y ascorbate is a b s o r b e d a n d f r o m w h i c h it is e l i m i n a t e d unchanged.
T w o other c o m p a r t m e n t s are e q u i l i b r a t e d w i t h the c e n t r a l
c o m p a r t m e n t . I n c o m p a r t m e n t 2 the m e t a b o l i s m is a s s u m e d to take p l a c e a n d f r o m this c o m p a r t m e n t metabolites are e l i m i n a t e d . C o m p a r t m e n t 3 is a d e e p p o o l t h a t acts as a storage c o m p a r t m e n t . D u r i n g the e x p e r i m e n t the p a r t i c i p a n t s l i m i t e d t h e i r d i e t a r y i n t a k e of ascorbate, p a r t i c u l a r l y b y a v o i d i n g fresh vegetables, c a n n e d f o o d , a n d other n u t r i e n t s k n o w n to h a v e a h i g h ascorbate content (e.g., p o t a t o e s ) . The
participants were
ascorbate
administered specially
prepared
capsules
of
several times d u r i n g the d a y to a c h i e v e a n e v e n a d m i n i s
t r a t i o n of doses. T h e r e c o m m e n d e d d i e t u n d o u b t e d l y l i m i t s t h e i n t a k e , b u t p a r t i c u l a r l y at the l o w e r dosages, r e l a t i v e l y s u b s t a n t i a l a m o u n t s of ascorbate m a y b e i n g e s t e d . mg/d)
T h e n o m i n a l intakes (30, 60, 90, a n d 180
therefore m a y not b e the a c t u a l intakes; a c c o r d i n g l y w e
have
m a d e a l l correlations to a t o t a l t u r n o v e r e s t i m a t e d f r o m the p l a s m a d e c a y curves r a t h e r t h a n to the a d m i n i s t e r e d a m o u n t s . T h e r e l a t i o n s h i p of t o t a l t u r n o v e r to p l a s m a l e v e l is s h o w n i n F i g u r e 3. I n this d i a g r a m w e h a v e also p l o t t e d l i t e r a t u r e d a t a w h e r e p l a s m a concentrations h a v e b e e n m e a s u r e d at w e l l - c o n t r o l l e d intakes. T h e r e is g o o d agreement
be
t w e e n the d a t a of o u r s t u d y a n d that of the l i t e r a t u r e . I n this r a n g e , the p l a s m a l e v e l of ascorbate c a n b e c o n s i d e r e d a g o o d i n d i c a t o r of
the
total turnover. T h e m o d e l u s e d a l l o w s the c a l c u l a t i o n of the t o t a l b o d y p o o l .
As
s h o w n i n T a b l e I , the t o t a l b o d y p o o l varies w i t h ascorbate i n t a k e a n d ranges b e t w e e n a b o u t 10 a n d 20 m g / k g b o d y w e i g h t . T h e ascorbate is a s s u m e d to be s o r b e d i n the r e n a l t u b u l i .
filtered
i n the g l o m e r u l i a n d r e a b
T h e r e n a l t u r n o v e r s u d d e n l y increases at a
c e r t a i n p l a s m a l e v e l ( F i g u r e 4 ) , i n d i c a t i n g a t h r e s h o l d v a l u e at w h i c h the t u b u l a r a b s o r p t i o n is e x c e e d e d b y the g l o m e r u l a r
filtration.
The renal
Figure 1. Radioactivity in plasma (6). Details of the absorption phase are shown under the diagonal line and the rapid decay during the washout phase is to the right of the vertical line. (Reproduced, with permission, from Ref. 6. Copyright 1979, American Journal of Clinical Nutrition.)
340
ASCORBIC
^
K
K12 ^
13
1
3 K
31
ACID
•
K
2
2 1
Figure 2. A schematic of the model (6). (Reproduced, with permission, from Ref. 6. Copyright 1979, American Journal of Clinical Nutrition.)
Table I. Concentration of Plasma Ascorbate, Calculated T o t a l Pool, and Half-Lives in the Groups Given Different Amounts of Ascorbate Dosage ( mg/d)
Plasma Ascorbate (mg/100 mL)
Total Pool (mg/kg body weight)
1 X30 1 X30 1 X30 1X30 2 X 30 2 X 30 2 X 30 2X45 2X45 2X45 4 X 45 4 X 45 4 X 45 4X45
0.24 0.52 0.41 0.72 0.78 0.73 0.79 0.83 0.80 0.98 1.12 1.15 0.95 1.16
11.4
—
13.7 19.6 20.7 17.0 15.2 14.7 16.4 12.6 21.6
—
19.3 20.0
(d) 40.1 16.5 28.9 26.5 27.0 23.1 25.8 9.1 12.6 17.0 12.8 12.7 7.9 10.5
16.
KAXLNER E T A L .
Kinetics of Ascorbic Acid
341
^(mg/100 mL) 1.8
t
0
1.6 0
1.4
1.2 0 °
A
0
1.0
O
•
O 0.8
n
o O
O A
0.6
•
0.4
0.2
( Intake ( m g / d ) '
TTOT
(mg/d)
0 0
50
100
150
Figure 3. Relationship between plasma level of ascorbate and intake turnover (bold symbols), and plasma level of ascorbate and total turnover (fine symbols). Data on intakes are literature data (6).
342
ASCORBIC
ACID
(mg/d)
TREN
i A
•
O
o
A
• o D
0 0.20
o
A 0.30
0.40
0.50
0.60
0.70
o
o
0.80
—0.90
c (mg/100 mL) ±
1.00
1.10
Figure 4. Renal turnover in relation to plasma concentration of ascorbate (6). (Reproduced, with permission, from Ref. 6. Copyright 1979, American Journal of Clinical Nutrition.)
1.20
16.
KALLNER
E T
A L .
343
Kinetics of Ascorbic Acid
t h r e s h o l d occurs a r o u n d a p l a s m a c o n c e n t r a t i o n of a b o u t 0.7-0.8 m g / 1 0 0 m L or a t o t a l t u r n o v e r of a b o u t 60 m g / d . H o w e v e r , i n subjects w i t h l o w ascorbate i n t a k e ( 1 X 30 m g / d ) , a c e r t a i n a m o u n t of u n c h a n g e d ascor b a t e is a l r e a d y excreted i n the u r i n e ( T a b l e I I ) .
Table II. Unchanged Ascorbate Recovered from U r i n e , in Relation to Total Amount of Radioactivity in the Urine, at Various Levels of O r a l Intake Dosage (mg/d) 1 2 2 4 4 4 2
X X X X X X X
30 30 45 45 250 500 1000
C-Ascorbate (%)
14
n 4 4 3 4 4 3 8
SEM
6.6 20.3 34.1 61.7 82.4 87.9 87.0
1.1 7.2 6.3 2.5 1.8 3.8 2.1
T h e t o t a l t u r n o v e r is the s u m of the r e n a l t u r n o v e r a n d the m e t a b o l i c turnover.
T h e m e t a b o l i c t u r n o v e r shows a s a t u r a t i o n at a b o u t
40-50
m g / d ( F i g u r e 5 ) , a n d this s a t u r a t i o n occurs at a t o t a l t u r n o v e r of a b o u t 60 m g / d . T h e s e values i m p l y t h a t u p to this t o t a l t u r n o v e r t h e m e t a b o l i c rate of ascorbate increases; the a s y m p t o t i c v a l u e c o u l d reflect t h e m a x i m u m p h y s i o l o g i c a l n e e d for ascorbate. T h e m a i n m e t a b o l i t e s of ascorbate i n the h u m a n b o d y are oxalate, d e h y d r o a s c o r b i c a c i d , 2 , 3 - d i k e t o g u l o n i c a c i d , a n d a s c o r b i c a c i d 2-sulfate. O f these, oxalate has a t t r a c t e d the most a t t e n t i o n b e c a u s e of the p o t e n t i a l h a z a r d f o r r e n a l c o m p l i c a t i o n s b y p r e c i p i t a t i o n of oxalate stones.
The
a b o v e - m e n t i o n e d m e t a b o l i c t u r n o v e r for ascorbate, w h i c h appears s a t u r a b l e , i n d i c a t e s that i n n o r m a l h u m a n s the a m o u n t of oxalate t h a t c a n b e f o r m e d is l i m i t e d . T h e r e f o r e , the o v e r a l l risk of i n d u c i n g oxalate p r e c i p i t a t i o n b y i n c r e a s i n g the i n t a k e of ascorbate p r o b a b l y is m i n u t e . T h e k i n e t i c m o d e l also a l l o w s the c a l c u l a t i o n of h a l f - l i v e s at v a r i o u s r e g i m e n s of ascorbate i n t a k e . T h e h a l f - l i v e s r a n g e f r o m 8 to 40 d ( T a b l e I).
T h e h a l f - l i v e s i n the l i t e r a t u r e or c a l c u l a t e d f r o m a v a i l a b l e i n f o r m a
t i o n c o r r e s p o n d to subjects o n a c o m p a r a t i v e l y l o w t o t a l t u r n o v e r , 2 0 - 4 0 m g / d , consistent w i t h the status of the subjects a n d t h e d i e t a r y r e g i m e n s that c o u l d b e a s s u m e d or w e r e d e f i n e d i n the e x p e r i m e n t a l set u p . r a n g e of h a l f - l i v e s also i n d i c a t e s t h a t the k i n e t i c b e h a v i o r of
The
ascorbate
is v e r y c o m p l i c a t e d a n d is r e l a t e d to the n u t r i t i o n a l status; for e x a m p l e , t h e c a l c u l a t e d h a l f - l i v e s are g e n e r a l l y l o n g e r o n l o w intakes t h a n o n higher (Table I ) .
A l t h o u g h B a k e r a n d his group ( 3 - 5 )
reported that
344
ASCORBIC
TMET 70
-
60
-
50
-
(mg/d)
t 1 1
o • 40
ACID
-
o •
o
D
A o
A
O 30
-
20
-
10
i
o A •
o
(mg/d)
TTOT
1 0
20
1 40
1
1
1
1
1
1
60
80
100
120
140
160
Figure 5. Metabolic turnover in relation to total turnover (6). (Reproduced, with permission, from Ref. 6. Copyright 1979, American Journal of Clinical Nutrition.) the pools d e c r e a s e d e x p o n e n t i a l l y , the course of the e l i m i n a t i o n seems to b e r e l a t e d to the t o t a l p o o l a n d thus t h e e l i m i n a t i o n is not a s i m p l e firsto r d e r one.
Gastrointestinal Absorption of Ascorbate The
g a s t r o i n t e s t i n a l a b s o r p t i o n of ascorbate s h o u l d b e c o n s i d e r e d
before s u m m a r i z i n g this s t u d y . I n n o case d i d w e a c h i e v e a c o m p l e t e r e c o v e r y of t h e a d m i n i s t e r e d r a d i o a c t i v e l y l a b e l e d a s c o r b i c a c i d .
In a
separate set of e x p e r i m e n t s ( 7 ) , the subjects w e r e e q u i l i b r a t e d o n a l i m i t e d i n t a k e of ascorbate a n d g i v e n a s m a l l o r a l dose of ascorbate t o g e t h e r w i t h a b o u t 30 m g of c a r r i e r ascorbate
1 4
C labeled
(7).
After
a f e w h o u r s this i n t a k e w a s f o l l o w e d b y l a r g e i n t a k e s of u n l a b e l e d
16.
KALLNER
ET
345
Kinetics of Ascorbic Acid
AL.
ascorbate a n d a l l u r i n e w a s c o l l e c t e d a n d a n a l y z e d u n t i l n o l a b e l w a s f o u n d i n the u r i n e , u s u a l l y d u r i n g a 10-d p e r i o d ( F i g u r e 6 ) . T h e subjects a b s o r b e d b e t w e e n 80 a n d 9 0 % of the a d m i n i s t e r e d l a b e l . T h e r e c o v e r y i n t h e k i n e t i c experiments w a s g e n e r a l l y l o w e r , p o s s i b l y b e c a u s e i n t h e a b s o r p t i o n s t u d y the d i s t r i b u t i o n of the a b s o r b e d l a b e l w a s i n c o m p l e t e , w h i c h leads to a m o r e efficient w a s h o u t of the l a b e l w i t h i n the p e r i o d of t h e e x p e r i m e n t .
T h u s a b e t t e r e s t i m a t i o n of t h e a b s o r b e d
amount
w o u l d b e a c h i e v e d b y m e a s u r i n g r e c o v e r y of l a b e l f r o m the u r i n e w i t h this e x p e r i m e n t a l d e s i g n t h a n i n the k i n e t i c e x p e r i m e n t . H o w e v e r , i n a l l cases the a b s o r p t i o n is i n c o m p l e t e at l o w a n d p h y s i o l o g i c a l levels.
High Risk Groups W i t h reference to the l i t e r a t u r e , d e c r e a s e d p l a s m a levels of ascorbate are f o u n d i n some groups of p e o p l e .
O n e s u c h g r o u p is t h e smokers, i n
w h i c h c o n s i d e r a b l y l o w e r p l a s m a levels h a v e b e e n o b s e r v e d a n d d o c u m e n t e d i n n u m e r o u s p u b l i c a t i o n s since the 1940s.
T h i s p r o m p t e d us to
select smokers as a risk g r o u p o n w h i c h a s i m i l a r k i n e t i c e x p e r i m e n t s h o u l d b e p e r f o r m e d a n d tested
(8).
T h e same p a r a m e t e r s as i n the s t u d y o n n o n s m o k e r s w e r e m e a s u r e d a n d c a l c u l a t e d . T h u s , i n the l o w e r r e g i o n , smokers r e q u i r e a h i g h e r t o t a l t u r n o v e r ( i n t a k e ) to r e a c h the same p l a s m a c o n c e n t r a t i o n as the n o n s m o k i n g g r o u p . T h e smokers' r e n a l h a n d l i n g of ascorbate w a s s i m i l a r to t h a t of the n o n s m o k e r s a n d the rate of g a s t r o i n t e s t i n a l a b s o r p t i o n w a s i n the same o r d e r of m a g n i t u d e , or a b o u t 7 5 % .
H o w e v e r , the smokers
f o r m e d a g r o u p of t h e i r o w n w h e n the m e t a b o l i c t u r n o v e r w a s r e l a t e d to the p l a s m a steady state c o n c e n t r a t i o n ( F i g u r e 7 ) , i n d i c a t i n g a n i n c r e a s e d m e t a b o l i c t u r n o v e r at c o m p a r a b l e steady state concentrations.
N o dif
ferences i n the t w o groups w e r e f o u n d i n the r e l a t i o n s h i p b e t w e e n the h a l f - l i f e a n d t o t a l t u r n o v e r . T h u s , the s m o k i n g h a b i t s seem to i n f l u e n c e just one of the l i n k s i n the c h a i n of events f r o m a b s o r p t i o n to e x c r e t i o n of ascorbate a n d this l i n k is the m e t a b o l i s m . T h e k i n e t i c m o d e l does n o t a l l o w a n y c o n c l u s i o n s o n the n a t u r e of the c h a n g e d m e t a b o l i s m .
Thus
w e c a n n o t differentiate b e t w e e n a c h a n g e d m e t a b o l i s m a n d a n increase i n the m e t a b o l i c rate a b o v e t h a t of the n o n s m o k e r .
H o w e v e r , the
find
ings m a y i n d i c a t e t h a t ascorbate has f u n c t i o n s i n the b o d y t h a t h a v e b e e n difficult to p r o v e , for e x a m p l e , i n the p r o t e c t i o n against or d e t o x i f i c a t i o n of noxious substances. A n u m e r i c a l t r e a t m e n t of t h e k i n e t i c d a t a o b t a i n e d i n the smokers s t u d y i n d i c a t e s t h a t to c o m p e n s a t e for the i n c r e a s e d m e t a b o l i c t u r n o v e r , smokers h a v e to increase t h e i r d a i l y i n t a k e b e y o n d t h a t of n o n s m o k e r s . B a s e d o n the same assumptions as i n the n o n s m o k e r s g r o u p , a n i n t a k e v a l u e of a b o u t 140 m g / d seems a p p r o p r i a t e .
i
1
1
Figure 6.
I
o
8
G N
o o
"5
1001
0
LS
>ooo
10
oo
(mL/min)
CIMET
1
t
o
0.5
•
A
X
1.0
X X
e
° X — •
1.5
* i (mg/100 mL)
o
2.0
Metabolic clearance as a function of plasma concentration of ascorbate. Bold symbols refer to nonsmokers.
10
15
CO
Ci
o
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H
w
w
348
ASCORBIC ACID
O t h e r risk g r o u p s a r e v a r i o u s stress g r o u p s since ascorbate a f u n c t i o n i n t h e biosynthesis of corticosteroids a n d other
fulfills
hormones.
S u c h studies a r e p l a n n e d b u t b e c a u s e of t h e n a t u r e of t h e e x p e r i m e n t a l setup, t h e y are n o t easily c a r r i e d o u t . O t h e r g r o u p s of p o t e n t i a l interest are a l c o h o l i c s , obese p e o p l e ,
a n d c e r t a i n d i s e a s e d o r i n j u r e d patients
w h e r e t h e m e t a b o l i c h a n d l i n g of ascorbate m a y b e w i d e l y different f r o m t h a t of n o r m a l h u m a n s . Conclusion In conclusion: • T h e b i o a v a i l a b i l i t y of i n g e s t e d ascorbate i n h e a l t h y n o n s m o k i n g males is s u b s t a n t i a l l y less t h a n 100% • T h e e l i m i n a t i o n of u n c h a n g e d a s c o r b i c a c i d v i a t h e k i d n e y s has a t h r e s h o l d v a l u e c o r r e s p o n d i n g t o a t o t a l t u r n o v e r of a b o u t 60 m g / d • T h e m e t a b o l i c t u r n o v e r levels a t a t o t a l t u r n o v e r of a b o u t 60 m g / d • T h e t o t a l b o d y p o o l c a n be i n c r e a s e d , r e a c h i n g a b o u t 20 m g / k g b o d y w e i g h t at a steady state c o n c e n t r a t i o n i n p l a s m a of 0.90 mg/100 m L , c o r r e s p o n d i n g to a t o t a l t u r n over of a b o u t 90 m g / d . T a k i n g a l l these observations i n t o a c c o u n t , a t o t a l i n t a k e of a b o u t 70-80 m g / d s h o u l d be t h e g o a l f o r n o n s m o k i n g h e a l t h y males. T h e statistical v a r i a t i o n o b s e r v e d i n d i c a t e s that a d a i l y i n t a k e of a b o u t 100 m g s h o u l d be a p p r o p r i a t e to c o v e r t h e needs of 9 5 % of t h e p o p u l a t i o n . F o r smokers the d a i l y ascorbate i n t a k e s h o u l d b e i n c r e a s e d to 140 m g / d . Literature Cited 1. "Recommended Dietary Allowances," 9th ed. National Academy of Sci ences, 1980, p. 75. 2. Lind, J. "Treatise on the Scurvy," 2nd ed., London, 1757. 3. Baker, E. M.; Saari, J. C.; Tolbert, B. M. Am. J. Clin. Nutr. 1966, 19, 371. 4. Baker, E. M.; Hodges, R. E.; Hood, J.; Sauberlich, H. E.; March, S. C. Am. J. Clin. Nutr. 1969, 22, 549. 5. Baker, E. M.; Hodges, R. E.; Hood, J.; Sauberlich, H. E.; March, S. C.; Canham, J. E. Am. J. Clin. Nutr. 1971, 24, 444. 6. Kallner, A.; Hartmann, D.; Hornig, D. Am. J. Clin. Nutr. 1979, 32, 530. 7. Kallner, A.; Hartmann, D.; Hornig, D. J. Vitam. Nutr. Res. 1977, 47, 383. 8. Kallner, A.; Hartmann, D.; Hornig, D. Am. J. Clin. Nutr. 1981, 32, 1347. 9. Kallner, A.; Hartmann, D.; Hornig, D. Int. J. Vitam. Nutr. Res. 1977, 47, 383. RECEIVED for review January 22, 1981.ACCEPTEDApril 15, 1981.
