Inorganic Chemistry in Biology and Medicine - ACS Publications

2 Possible Functions and Medical Significance of the Abstruse Trace Metals FORREST H. NIELSEN

Downloaded by UNIV LAVAL on April 9, 2016 | http://pubs.acs.org Publication Date: December 22, 1980 | doi: 10.1021/bk-1980-0140.ch002

United States Department of Agriculture, Science and Education Administration, Human Nutrition Laboratory, Grand Forks, ND 58202 Since 1970, a number of reports have suggested that s e v e r a l metals present i n minute q u a n t i t i e s i n animal t i s s u e s are e s s e n t i a l n u t r i e n t s . The t r a c e metals i n c l u d e cadmium, l e a d , n i c k e l , t i n and vanadium. Findings suggesting that cadmium, lead and t i n are e s s e n t i a l have come from one laboratory (1,2,3) and have not been confirmed i n another laboratory. Minor growth depression i n suboptimally growing r a t s was the main c r i t e r i o n f o r demonstrating the e s s e n t i a l i t y of cadmium, lead and t i n . That c r i t e r i o n i s of questionable p h y s i o l o g i c a l s i g n i f i c a n c e . The evidence i s more s u b s t a n t i a l f o r the e s s e n t i a l i t y of n i c k e l and vanadium. A l s o , apparent progress has been made i n determining e s s e n t i a l functions f o r those elements. Thus, i n t h i s chapter the p o s s i b l e medical s i g n i f i c a n c e and e s s e n t i a l functions of n i c k e l and vanadium are emphasized. Nickel Essentiality. N i c k e l i s an e s s e n t i a l n u t r i e n t f o r animals and probably f o r humans. Signs of n i c k e l d e p r i v a t i o n have been described f o r f i v e animal species - c h i c k , r a t , m i n i p i g , goat and sheep. B r i e f l y , the signs of d e f i c i e n c y i n c l u d e the following: I (4) reported that the signs of n i c k e l d e p r i v a t i o n i n chicks included depressed l e v e l s of l i v e r phospholipids, o x i d a t i v e a b i l i t y of the l i v e r i n the presence of αglycerophosphate, yellow lipochrome pigments i n the shank s k i n , hematocrits and u l t r a s t r u c t u r a l abnormalities i n the l i v e r . I (5) found the signs of n i c k e l d e p r i v a t i o n i n the r a t i n c l u d e d elevated p e r i n a t a l m o r t a l i t y , u n t h r i f t i n e s s c h a r a c t e r i z e d by a rough coat and/or uneven h a i r development i n the young, pale l i v e r s , elevated rate of a-glycerophosphate o x i d a t i o n by l i v e r homogenates, and u l t r a s t r u c t u r a l changes i n the l i v e r . N i c k e l d e p r i v a t i o n a l s o apparently depressed growth and hematocrits, but these signs were not c o n s i s t e n t l y s i g n i f i c a n t , e s p e c i a l l y i n adult r a t s . In a s e r i e s of s t u d i e s , This chapter not subject to U.S. copyright. Published 1980 American Chemical Society

Martell; Inorganic Chemistry in Biology and Medicine ACS Symposium Series; American Chemical Society: Washington, DC, 1980.


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INORGANIC CHEMISTRY IN BIOLOGY A N D M E D I C I N E

summarized r e c e n t l y , Schnegg and Kirchgessner ( 6 ) developed a set of n i c k e l d e p r i v a t i o n signs f o r the r a t that appear divergent to those of N i e l s e n et a l . ( 5 ) . Schnegg and Kirchgessner found t h a t , at age 3 0 days, r a t s e x h i b i t e d s i g n i f i c a n t l y depressed growth, hematocrits, hemoglobin l e v e l s , e r y t h r o c y t e counts, l e v e l s of urea, ATP and glucose i n serum, l e v e l s of t r i g l y c e r i d e s , glucose and glycogen i n l i v e r , l e v e l s of i r o n , copper and z i n c i n l i v e r , kidney and spleen, and a c t i v i t i e s of s e v e r a l l i v e r and kidney enzymes. They a l s o found that the signs of n i c k e l d e p r i v a t i o n were l e s s severe i n o l d e r r a t s and i n r a t s f e d 1 0 0 yg i n s t e a d of 5 0 yg of i r o n / g of diet. Schnegg and Kirchgessner suggested that some of the signs r e s u l t e d from impaired i r o n absorption induced by n i c k e l deprivation. Anke et a l . (_7 , J 3 ) found that n i c k e l - d e p r i v e d minipigs and goats e x h i b i t e d depressed growth, delayed e s t r u s , elevated p e r i n a t a l m o r t a l i t y , u n t h r i f t i n e s s c h a r a c t e r i z e d by a rough coat and s c a l y and crusty s k i n , depressed l e v e l s of calcium i n the s k e l e t o n and of z i n c i n l i v e r , h a i r , r i b and b r a i n . Spears et a l . ( 9 , 1 0 ) found that n i c k e l - d e p r i v e d lambs showed depressed growth, t o t a l serum p r o t e i n s , e r y t h r o c y t e counts, and t o t a l l i p i d s and c h o l e s t e r o l i n l i v e r , and copper i n l i v e r . Iron contents were elevated i n l i v e r , spleen, lung and b r a i n . The discussed f i n d i n g s show that n i c k e l meets the requirements f o r e s s e n t i a l i t y as defined by Mertz ( 1 1 ) . That d e f i n i t i o n s t a t e s that an element i s e s s e n t i a l i f i t s d e f i c i e n c y r e p r o d u c i b l y r e s u l t s i n impairment of a f u n c t i o n from optimal to suboptimal. B i o l o g i c a l Function. The evidence showing that n i c k e l i s e s s e n t i a l does not c l e a r l y define i t s metabolic f u n c t i o n . However, recent f i n d i n g s show that n i c k e l may f u n c t i o n as a c o f a c t o r or s t r u c t u r a l component i n s p e c i f i c metalloenzymes or m e t a l l o p r o t e i n s , or as a b i o l i g a n d c o f a c t o r f a c i l i t a t i n g the i n t e s t i n a l absorption of the F e ( I I I ) i o n . Himmelhoch et a l . ( 1 2 ) were f i r s t to report f i n d i n g s suggesting that n i c k e l has a r o l e as a s t r u c t u r a l component of a metalloprotein. They f r a c t i o n a t e d human serum by column chromatography and found a m e t a l l o p r o t e i n that contained n i c k e l , but nondetectable l e v e l s of Ca, Mg, S r , Ba, Fe, Zn and Mn. Nomoto jet a l . ( 1 3 ) used a technique b a s i c a l l y the same as that of Himmelhoch et: a l . t o demonstrate the presence of a n i c k e l c o n t a i n i n g macroglobulin, which they named " n i c k e l o p l a s m i n " , i n r a b b i t serum. Subsequently, Sunderman ejt a l . ( 1 4 ) i s o l a t e d n i c k e l o p l a s m i n from human serum. O r i g i n a l l y , Sunderman et a l . ( 1 4 ) s t a t e d that the n i c k e l o p l a s m i n of humans and r a b b i t s was an a2-macroglobulin. L a t e r , however, immunologic studies by Nomoto et_ a l . ( 1 5 ) i n d i c a t e d that r a b b i t serum nickeloplasmin r e a c t s as an a\-macroglobulin that i s apparently homologous to human a - m a c r o g l o b u l i n . They cautioned, however, that the 2


2.

Abstruse

NIELSON

Trace

25

Metals

apparent r e l a t i o n s h i p between r a b b i t ai-macroglobulin and human 012-macroglobulin was complicated when Saunders ejt a l . (16) found that f i v e components of human a2-macroglobulin can be d i s t i n g u i s h e d on the b a s i s of e l e c t r o p h o r e t i c and enzyme-binding p r o p e r t i e s . Other c h a r a c t e r i s t i c s of nickeloplasmin were an estimated molecular weight of 7.0 x 10 , n i c k e l content of 0.90 g atoms/mole, p o s i t i v e r e a c t i o n to p e r i o d i c a c i d S c h i f f s t a i n f o r g l y c o p r o t e i n s , and e s t e r o l y t i c a c t i v i t y (on the b a s i s of i t s c a p a c i t y to hydrolyze t r i t i a t e d t o s y l - a r g i n i n e methyl e s t e r at a pH of 7.5 i n t r i s - H C l b u f f e r ) (14,15). Decsy and Sunderman (17) found that the n i c k e l i n n i c k e l o p l a s m i n was not r e a d i l y exchangeable with N i ( I I ) i n v i v o or i n v i t r o . I t was necessary to administer a r e l a t i v e l y l a r g e dose of N i ( I I ) to obtain r a p i d l a b e l l i n g of serum n i c k e l o p l a s m i n . Decsy and Sunderman (17) o f f e r e d two p o s s i b l e explanations f o r t h e i r f i n d i n g s . One was that n i c k e l occurs i n a d i f f e r e n t valence s t a t e , such as N i ( I I I ) , when bound to n i c k e l o p l a s m i n , and thus, l a b e l l i n g of nickeloplasmin was l i m i t e d by the i n v i v o o x i d a t i o n of N i ( I I ) to the r e q u i s i t e valence. The other p o s s i b i l i t y was that n i c k e l o p l a s m i n p r e f e r e n t i a l l y binds n i c k e l as an organic complex that i s not synthesized r e a d i l y by the r a b b i t jLn v i v o . The f i n d i n g s of Decsy and Sunderman (17) suggested that n i c k e l o p l a s m i n was a ternary complex of serum ai-macroglobulin with a N i - c o n s t i t u e n t of serum. Sunderman (18) noted that Haupt et: a l . (19) i s o l a t e d from human serum a 9.55-oti-glycoprotein that s t r o n g l y bound N i ( I I ) and thus suggested that n i c k e l o p l a s m i n might represent a complex of the 9.55-ai-glycoprotein with serum ai-macroglobulin. To date, there i s no c l e a r i n d i c a t i o n as to the p h y s i o l o g i c a l s i g n i f i c a n c e or f u n c t i o n of n i c k e l o p l a s m i n . The hypothesis that n i c k e l i n animals may f u n c t i o n as an enzyme c o f a c t o r has been stimulated by the discovery that urease from s e v e r a l p l a n t s and microorganisms i s a n i c k e l metalloenzyme (20-25). Dixon et a l . (20) found that h i g h l y p u r i f i e d urease (E.C.3.5.1.5) from j a c k beans (Canavalia e n s i f o r m i s ) contained s t o i c h i o m e t r i c amounts of n i c k e l , 2 . 0 + 0 . 3 g atom of n i c k e l per 105,000 g of enzyme. The a c t i v e s i t e n i c k e l i o n was t i g h t l y bound, being s i m i l a r to the z i n c i o n i n yeast a l c o h o l dehydrogenase (E.C.1.1.1.1) and manganous i o n i n chicken l i v e r pyruvate carboxylase (E.C.6.4.1.1). Jack bean urease was s t a b l e and f u l l y a c t i v e i n the presence of 0.5 mM EDTA at n e u t r a l pH. The n i c k e l i o n was removed only upon exhaustive d i a l y s i s i n the presence of c h e l a t i n g agents (21), and then i t was not p o s s i b l e to r e s t o r e n i c k e l with r e c o n s t i t u t i o n of enzymatic a c t i v i t y . Jack bean urease has r e l a t i v e l y low r e a c t i v i t y of the a c t i v e - s i t e s u l f h y d r y l group (26). According to Dixon ^ t a l . (21), t h i s could be explained by c o o r d i n a t i o n of the a c t i v e - s i t e n i c k e l with the unreactive cysteine. The b i o l o g i c a l r o l e of urease apparently i s the conversion 5

6 3


6 3

6 3



26

INORGANIC CHEMISTRY

IN BIOLOGY

AND

MEDICINE

of urea to i n o r g a n i c ammonia that can be used by p l a n t s ( 2 4 , 2 5 ) . Dixon et a l . ( 2 1 ) suggested the f o l l o w i n g mechanism f o r that conversion: The amide n i t r o g e n of urea coordinates with the enzyme-bound n i c k e l . N u c l e o p h i l i c attack or general base c a t a l y s i s by a s u i t a b l e a c t i v e - s i t e group would then lead to an a c t i v e - s i t e , nickel-ammonia complex. Thus, a s p e c i f i c b i o l o g i c a l r o l e i s known f o r n i c k e l i n plants. No such s p e c i f i c r o l e has been defined f o r animals. N i c k e l can a c t i v a t e many enzymes i n v i t r o (Table I ) , but i t s r o l e as a s p e c i f i c c o f a c t o r f o r any enzyme has not been shown i n animals. The s p e c i f i c manner i n which n i c k e l acts i n animals i s unknown, but recent f i n d i n g s suggest that i t has a r o l e i n the p a s s i v e absorption of the F e ( I I I ) i o n . I found i n r a t s that the form of d i e t a r y i r o n might e x p l a i n the apparent d i f f e r e n c e s i n data f o r growth and hematocrits between my e a r l y s t u d i e s ( 5 ) and the s t u d i e s of Schnegg and Kirchgessner ( 6 ) . In my e a r l y s t u d i e s ( 5 ) , I s u p p l i e d 5 0 yg of i r o n / g of d i e t as i r o n sponge d i s s o l v e d i n H C 1 (determined to be f e r r i c c h l o r i d e ) , whereas Schnegg and Kirchgessner ( 6 ) s u p p l i e d 5 0 yg of i r o n / g of d i e t as the s u l f a t e . Schnegg and Kirchgessner i n d i c a t e d , by p e r s o n a l communication, that they had used ferrous s u l f a t e , but I ( 2 7 ) could not o b t a i n growth and hematocrit f i n d i n g s s i m i l a r to t h e i r s unless i r o n was s u p p l i e d as f e r r i c s u l f a t e . When I s t u d i e d the r e l a t i o n s h i p between n i c k e l and i r o n f u r t h e r i n f a c t o r i a l l y designed experiments, n i c k e l and i r o n i n t e r a c t e d to a f f e c t hematocrit and hemoglobin, but apparently only when d i e t a r y i r o n was mostly i n a r e l a t i v e l y u n a v a i l a b l e form, such as f e r r i c s u l f a t e . In three experiments, female weanling r a t s were fed a b a s a l d i e t c o n t a i n i n g about 10 ng of n i c k e l and 2 . 3 yg of i r o n / g and supplemented w i t h graded l e v e l s of n i c k e l and i r o n . Iron was supplemented to the d i e t at 0 , 2 5 , 5 0 and 1 0 0 yg/g i n a l l experiments. Iron was s u p p l i e d as F e 2 (S0t+) 3-n^O in Experiments 1 and 3 , and as a mixture of 40% F e S 0 i + n H 2 0 and 60% F e ( S 0 ) - n H 0 i n Experiment 2 . An e x t r a l e v e l , 1 2 . 5 yg/g, was added i n Experiment 3 . In a l l experiments, n i c k e l was supplemented to the d i e t at 0 , 5 and 5 0 yg/g. A f t e r 9 - 1 0 weeks, e s p e c i a l l y when the d i e t a r y i r o n supplement was only f e r r i c s u l f a t e , the i n t e r a c t i o n between i r o n and n i c k e l a f f e c t e d s e v e r a l parameters examined. Data f o r hematocrit and hemoglobin appear i n Tables I I and I I I . In Experiments 1 and 3 , when d i e t a r y f e r r i c s u l f a t e was low, hematocrit and hemoglobin were lower i n n i c k e l - d e p r i v e d than -supplemented r a t s , e s p e c i a l l y when i r o n / g of d i e t was 2 5 yg. Experiment 1 n i c k e l - d e p r i v e d r a t s had an average hematocrit of 3 6 . 3 % and hemoglobin l e v e l of 1 0 . 0 9 g / 1 0 0 ml, whereas r a t s fed n i c k e l at 5 and 5 0 yg/g of d i e t had hematocrits of 4 0 . 8 % and 4 2 . 0 % and hemoglobin l e v e l s of 1 1 . 7 7 and 1 2 . 0 9 g / 1 0 0 ml, r e s p e c t i v e l y . In Experiment 3 , n i c k e l - d e p r i v e d r a t s had an average hematocrit of 2 6 . 8 % and #

2

l +

3

2


NIELSON

Abstruse

Trace

Metals

Table I Enzymes " a c t i v a t e d " by n i c k e l


Enzyme

A c e t y l coenzyme A synthetase

6.2.1.1

Amino a c i d Amylase. Arginase

3.2.1.1 3.5.3.1.

decarboxylase

A s c o r b i c a c i d oxidase ATPase (14s, 30s dynein) 3,4 Benzpyrene h y d r o x y l a s e Carboxypeptidase Citritase Deoxyribonuclease I Desoxyribonuclease Enolase Esterase Hexokinase H i s t i d i n e decarboxylase Oxalacetic carboxylase Pepsin Phosphodeoxyribomutase Phosphoglucomutase Phospholipase A Phosphorylase phosphatase Protease P y r i d o x a l phosphokinase Pyruvate k i n a s e P y r u v i c a c i d oxidase Ribonuclease R i b u l o s e diphosphate carboxylase Thiaminokinase Trypsin Tyrosinase

1.10.3.3 3.6.1.1.14.14.2 3.4.12.4.1.3.6 3.1.4.5 3.1.4.4.2.1.11

Urease

3.5.1.5

Compiled

Source

E.C. No.

-

2.7.1.1 4.1.1.22

-

3.4.23.1 2.7.5.6 2.7.5.5 3.1.1.3.1.3.17 3.4.— 2.7.1.35 2.7.1.40 1.2.3.4 3.1.4.4.1.1.39 2.7.6.2 3.4.21.4 1.14.18.1

Bovine h e a r t mitochondria E. c o l i , C. w e l c h i i Human s a l i v a Bovine l i v e r Canavalia ensiformis Jack bean Yeast Broad bean l e a f Tetrahymena c i l i a Lung

Bovine pancreas Bovine thymus Porcine l i v e r Yeast L a c t o b a c i l l u s 30a Parsley root P o r c i n e mucosa E. c o l i Rabbit muscle C r o t a l u s a t r o x venom Bovine a d r e n a l c o r t e x Human s e n i l e lens R a b b i t muscle Proteus v u l g a r i s Bovine pancreas Spinach Rat

liver

Mouse melanoma Potato Jack bean Lemna p a u c i c o s t a t a Rumen b a c t e r i a l Soybean

by N i e l s e n ( 3 3 ) .


INORGANIC CHEMISTRY IN BIOLOGY A N D MEDICINE

Table II Effects on rats of nickel, iron, and their interaction on hematocrits


Treatment

a

Hematocrit

Ni

Fe

ug/g

yg/g

0 0 0 0 0

0 12.5 25 50 100

5 5 5 5 5

0 12.5 25 50 100

50 50 50 50 50

0 12.5 25 50 100

Experiment 1

Experiment 2

Experiment 3

% 14.3

18.1

36.3-

42.2

41.9 42.1

42.4 41.8

15.2

19.3

-

-

40.8 42.3 42.0

41.6 41.9 41.5

20.1

20.4

42.0

41.1-

40.5 41.3

42.2 42.2

14.2 22.1 26.8 38.3 39.1 17.0 25.8 32.1 38.9 39.3 16.0 23.2 33.8 39.0 40.2

Analysis of Variance - P Values Nickel effect Iron effect Nickel x iron Error mean square (df)

0.002 0.0001 0.0001 2.8(70)

.01 .0001 NS 1.6(58)

.0001 .0001 .006 4.9(75)

3.3

6.4

4.1

1.1

2.1

1.4

0.8

-

1.2

-

1.2

-

Scheffe values** Treatment means 6 s-test 6 Iron effect means 18 s-test 18 Nickel effect means 24 s-test 24 Nickel effect means 30 s-test 30

l e v e l s of supplements i n diet: Ni (nickel chloride) and Fe ( f e r r i c sulfate) i n Experiments 1 and 3; Fe was a mixture of 40% ferrous and 60% f e r r i c sulfate i n Experiment 2. ^The Scheffe test (28) i s a method for performing multiple comparisons between group means. Means d i f f e r i n g by more than the value given are s i g n i f i c a n t l y different (P < 0.05). As i t assumes a l l possible comparisons are performed, i t i s regarded as a conservative test.


NIELSON

Abstruse

Trace

Metals

Table I I I Effects on rats of n i c k e l , iron, and their interaction on hemoglobin levels


Treatment

Hemoglobin Level

Ni

Fe

yg/g

yg/g

0 0 0 0 0

0 12.5 25 50 100

5 5 5 5 5

0 12.5 25 50 100

50 50 50 50 50

0 12.5 25 50 100

Experiment 1

Experiment 2 g/100

ml

2.65

3.73

10.09

13.27

12.65 13.05

13.42 13.23

3.03 11.77 12.98 13.07

-

Experiment 3

4.08 13.15 13.26 13.13

-

3.88

4.46

12.09

13.01

12.62 12.80

13.29 13.26

2.55 4.90 6.19 10.85 11.61 3.36 5.81 8.31 10.92 11.41 2.95 5.01 8.92 11.13 11.65

Analysis of Variance - P Values Nickel effect Iron effect Nickel x iron Error mean square (df) Scheffe values*

.003 .0001 .0001 0.31(71)

.003 .0001 NS 0.16(58)

.0002 .0001 .0002 0.56(75)

5

Treatment means 6 s-test 6 Iron effect means 18 s-test 18 Nickel effect means 24 s-test 24 Nickel effect means 30 s-test 30

1.04

2.14

1.38

0.34

0.71

0.47

0.25

-

0.42

0.41

-

l e v e l s of supplements i n diet: Ni (nickel chloride) and Fe ( f e r r i c sulfate) i n Experiments 1 and 3; Fe was a mixture of 40% ferrous and 60% f e r r i c sulfate in Experiment 2. The Scheffe test (28) i s a method for performing multiple comparisons between group means. Means d i f f e r i n g by more than the value given are s i g n i f i c a n t l y different (P < 0.05). As i t assumes a l l possible comparisons are performed, i t i s regarded as a conservative test.



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hemoglobin l e v e l of 6.19 g/100 ml; whereas rats fed n i c k e l at 5 and 50 yg/g of d i e t had hematocrits of 32.1% and 33.8% and hemoglobin l e v e l s of 8.31 and 8.92 g/100 ml, r e s p e c t i v e l y . The d i f f e r e n c e between n i c k e l - d e p r i v e d and supplemented r a t s i n Experiments 1 and 3 were s i g n i f i c a n t by the Scheffe t e s t (28). D i e t a r y n i c k e l apparently d i d not a f f e c t hematocrit or hemoglobin when the d i e t contained 100 yg of i r o n / g . N i c k e l and i r o n d i d not i n t e r a c t to a f f e c t hematocrit and hemoglobin when i r o n was s u p p l i e d as f e r r i c - f e r r o u s s u l f a t e . The form of d i e t a r y i r o n a l s o i n f l u e n c e d the e f f e c t of n i c k e l on hematocrit and hemoglobin. When f e r r i c s u l f a t e was fed (Experiments 1 and 3 ) , both parameters were s i g n i f i c a n t l y lower i n n i c k e l - d e p r i v e d than -supplemented r a t s . In Experiment 2 the e f f e c t of n i c k e l was much l e s s marked than i n Experiments 1 and 3. In Experiment 2, the greatest d i f f e r e n c e was i n r a t s f e d no supplemental i r o n . There were some d i f f e r e n c e s between Experiments 1 and 3, e s p e c i a l l y when the d i e t contained 25 or 50 yg of i r o n / g . In Experiment 3, hematocrit and hemoglobin l e v e l s were s i g n i f i c a n t l y depressed i n a l l groups fed 25 yg i r o n / g of d i e t , although the depression was l e s s severe i n nickel-supplemented than -deprived r a t s . In Experiment 1, with 25 yg of i r o n / g of d i e t , hematocrit and hemoglobin were depressed only i n n i c k e l deprived r a t s ; values were near normal i n r a t s f e d 5 or 50 yg of n i c k e l / g of d i e t . In Experiment 3, the hematocrit and hemoglobin data i n d i c a t e d that r a t s f e d 50 yg of i r o n / g of d i e t as f e r r i c s u l f a t e were s t i l l s l i g h t l y i r o n - d e f i c i e n t . In Experiment 1, hematocrit and hemoglobin apparently were normal i n r a t s f e d 50 yg of i r o n / g of d i e t . P o s s i b l y , the i r o n supplement was most h i g h l y contaminated with the ferrous form i n Experiment 1. The i r o n supplement was a s c e r t a i n e d to be 92% i n the f e r r i c form i n Experiment 3, but was not tested i n Experiment 1. The observations that the form of d i e t a r y i r o n apparently a f f e c t e d the response of r a t s to n i c k e l d e p r i v a t i o n and n i c k e l and i r o n i n t e r a c t e d suggest that n i c k e l a f f e c t s i r o n absorption. The apparent dependence of that i n t e r a c t i o n upon the r e l a t i v e l y i n s o l u b l e f e r r i c s a l t suggests that n i c k e l has a r o l e i n the absorption of the F e ( I I I ) i o n . F e ( I I I ) s a l t s are extremely i n s o l u b l e i n n e u t r a l / a l k a l i n e b i o f l u i d s (29). Thus, f o r absorption by the duodenum, the F e ( I I I ) must be complexed, or converted t o the more s o l u b l e F e ( I I ) form. According to May et a l . (29), only l i g a n d s , such as p o r p h y r i n - l i k e molecules, that form h i g h - s p i n complexes and thereby i n c r e a s e the e l e c t r o d e p o t e n t i a l s t a b i l i z e F e ( I I ) over F e ( I I I ) . Most other b i o l i g a n d s lower the e l e c t r o d e p o t e n t i a l and thus enhance the s t a b i l i t y of the F e ( I I I ) s t a t e . T h e r e f o r e , the p r e f e r r e d chelated s t a t e of i r o n jLn v i v o i s probably F e ( I I I ) and the r e d u c t i o n to F e ( I I ) occurs spontaneously only i n the presence of high l o c a l concentrations of a reducing m e t a b o l i t e , or under the i n f l u e n c e



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of s p e c i a l enzyme mechanisms. N i c k e l might i n t e r a c t with i r o n through one of those mechanisms but probably does not. The f i n d i n g that 50 yg of n i c k e l / g of d i e t was not much b e t t e r than 5 yg i n improving hematocrits and hemoglobin l e v e l s i n n i c k e l deprived r a t s fed low l e v e l s of i r o n as f e r r i c s u l f a t e i s apparently i n c o n s i s t e n t with the p o s s i b i l i t y that n i c k e l acts as, or p a r t of, a reducing agent converting F e ( I I I ) to F e ( I I ) . The i d e a that n i c k e l might act i n a s p e c i a l enzyme mechanism that converts F e ( I I I ) to Fe(II) i s a t t r a c t i v e , but no such mechanism i s known. The most a t t r a c t i v e p o s s i b i l i t y i s that n i c k e l promotes the absorption of F e ( I I I ) per se by enhancing i t s complexation to a l i p o p h i l i c molecule. Evidence shows that both a c t i v e and passive t r a n s p o r t mechanisms have r o l e s i n i r o n absorption. A c t i v e transport to the s e r o s a l surface i s r e l a t i v e l y s p e c i f i c f o r the d i v a l e n t c a t i o n (30), which i n d i c a t e s that the F e ( I I I ) i o n i s absorbed by passive t r a n s p o r t . Passive transport i s d i f f u s i o n - c o n t r o l l e d and only permits the t r a n s i t of l i p o p h i l i c molecules. S u b s t a n t i a l evidence shows l i p o p h i l i c F e ( I I I ) complexes t r a v e r s e biomembranes i n the same manner as l i p o p h i l i c complexes of other metals. N i c k e l could a f f e c t the metabolism of the l i p o p h i l i c F e ( I I I ) complexes i n at l e a s t two ways. N i c k e l might e i t h e r act i n an enzymatic r e a c t i o n that forms a l i p o p h i l i c i r o n transport molecule or simply preserve a transport l i g a n d , such as c i t r a t e , by complexing with i t u n t i l replaced by the F e ( I I I ) i o n . The hypothesis that n i c k e l has a r o l e i n the passive d i f f u s i o n of F e ( I I I ) i s supported by my data f o r hematocrit and hemoglobin discussed p r e v i o u s l y . Dowdle et a l . (31) suggested that the a c t i v e transport mechanism f o r i r o n would become important i f passive d i f f u s i o n were r e s t r i c t e d . Thus, at the lower l e v e l s of i r o n supplementation as a f e r r i c - f e r r o u s mixture, there was some ferrous ions a v a i l a b l e f o r a c t i v e t r a n s p o r t , and n i c k e l d e p r i v a t i o n d i d not s i g n i f i c a n t l y a f f e c t l e v e l s of hematocrit or hemoglobin. On the other hand, when only f e r r i c i r o n was fed, the a c t i v e t r a n s p o r t mechanism could not operate, and i n n i c k e l d e p r i v a t i o n , the passive d i f f u s i o n of l i p o p h i l i c F e ( I I I ) complexes apparently was i n h i b i t e d . As a r e s u l t , l e v e l s of hematocrit and hemoglobin d i f f e r e d between n i c k e l - d e p r i v e d and -supplemented r a t s at low l e v e l s of i r o n supplementation. At high l e v e l s of supplementation, perhaps there was enough F e ( I I ) present i n the d i e t to prevent any d i f f e r e n c e s as the i r o n supplement was approximately 92% F e ( I I I ) . Medical S i g n i f i c a n c e . An i n i t i a l impression i s that n i c k e l n u t r i t u r e would not be of p r a c t i c a l s i g n i f i c a n c e . I (4) reported that 50 yg of n i c k e l / k g of d i e t s a t i s f i e d the d i e t a r y n i c k e l requirement of c h i c k s , and Schnegg and Kirchgessner (6) reported a s i m i l a r requirement f o r r a t s . I f animal data were extrapolated to man, the d i e t a r y n i c k e l requirement of humans



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would probably be i n the range of 16-25 yg/1000 C a l (32) . L i m i t e d s t u d i e s i n d i c a t e that the o r a l intake of n i c k e l by humans ranges between 170 and 700 yg per day (33) which would be ample to meet the hypothesized n i c k e l requirement. However, the f i n d i n g that n i c k e l may be important i n the absorption and metabolism of i r o n might help define s i t u a t i o n s i n which n i c k e l would have medical s i g n i f i c a n c e . I am d e f i n i n g medical s i g n i f i c a n c e as the u n i n t e n t i o n a l production of a n u t r i t i o n a l d i s o r d e r i n humans. P o s s i b l y f o r i n d i v i d u a l s who consume u n a v a i l a b l e , or d e f i c i e n t amounts of, i r o n , or have an elevated need f o r i r o n , n i c k e l n u t r i t u r e might be of concern. For example, many women consume inadequate i r o n . N i c k e l a l l e r g y i s a common d i s o r d e r . About 10% of tested i n d i v i d u a l s reacted p o s i t i v e l y to the n i c k e l - p a t c h t e s t and incidence was highest among women (34). Because recent reports i n d i c a t e that d i e t a r y n i c k e l may be important i n hand-eczema caused by n i c k e l (35,36) , one treatment f o r n i c k e l a l l e r g y i s reduction of d i e t a r y n i c k e l . E x t r a p o l a t i o n from animal f i n d i n g s suggests that care should be exercised with such treatment to assure that proper n i c k e l and i r o n n u t r i t u r e i s maintained to avoid adverse consequences. Vanadium Essentiality. Evidence f o r the n u t r i t i o n a l e s s e n t i a l i t y of vanadium i s not c o n c l u s i v e . S t r a s i a (37) found that r a t s fed l e s s than 100 ng of vanadium/g of d i e t e x h i b i t e d slower growth, higher plasma and bone i r o n , and higher hematocrits than c o n t r o l s fed 0.5 yg of vanadium/g of d i e t . However, Williams (38) was unable to d u p l i c a t e the f i n d i n g s of S t r a s i a (37), even i n the same l a b o r a t o r y under s i m i l a r c o n d i t i o n s . Schwarz and M i l n e (39) reported that a vanadium supplement of 25 to 50 yg/100 g of a s e m i - p u r i f i e d d i e t gave a p o s i t i v e growth response i n r a t s . On the other hand, Hopkins and Mohr (40) reported that the only e f f e c t of vanadium d e p r i v a t i o n on r a t s was an apparent impaired reproductive performance (decreased f e r t i l i t y and increased p e r i n a t a l m o r t a l i t y ) that became apparent only i n the f o u r t h generation. Studies with chicks a l s o gave i n c o n s i s t e n t signs of d e f i c i e n c y . Hopkins and Mohr (41,42) found that vanadiumdeprived chicks e x h i b i t e d s i g n i f i c a n t l y depressed wing and t a i l f e a t h e r development, depressed plasma c h o l e s t e r o l at age 28 days, elevated plasma c h o l e s t e r o l at age 49 days, and, i n a subsequent study (40), elevated plasma t r i g l y c e r i d e s at age 28 days. I reported that vanadium-deprivation depressed growth, elevated hematocrits and plasma c h o l e s t e r o l , and adversely a f f e c t e d bone development (43). I became concerned about the i n c o n s i s t e n c y of the e f f e c t of vanadium d e p r i v a t i o n on chicks and r a t s , and attempted to e s t a b l i s h a d e f i n i t e set of signs of vanadium d e p r i v a t i o n f o r these s p e c i e s . In 16 experiments, i n which chicks were fed



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s e v e r a l d i e t s of d i f f e r e n t composition, vanadium d e p r i v a t i o n adversely a f f e c t e d growth, f e a t h e r i n g , hematocrits, plasma c h o l e s t e r o l , bone development, and the l e v e l s of l i p i d , phospholipid and c h o l e s t e r o l i n l i v e r . In s e v e r a l experiments with r a t s , vanadium d e p r i v a t i o n adversely a f f e c t e d p e r i n a t a l s u r v i v a l , growth, p h y s i c a l appearance, hematocrits, plasma c h o l e s t e r o l , and l i p i d s and phospholipids i n l i v e r . Unfortunately, no s i g n of vanadium d e p r i v a t i o n i n c h i c k s , or r a t s , was found c o n s i s t e n t l y throughout a l l experiments. Apparently i n c o n s i s t e n c y of vanadium d e p r i v a t i o n signs i s r e l a t e d to the f a c t that vanadium metabolism i s s e n s i t i v e to changes i n the composition of the d i e t (44). Perhaps d i e t composition a f f e c t s the form of d i e t a r y vanadium. Vanadium has a r i c h and v a r i e d chemistry, e s p e c i a l l y i n the (IV) and (V) s t a t e . The form of vanadium, u s u a l l y an oxyanion ( i . e . VO3"", V 0 ) , depends upon i t s concentration i n , and pH o f , the medium (45). Perhaps, one form i s more r e a d i l y a v a i l a b l e f o r absorption, or a c t i v e i n metabolism, than another. Thus, a d i e t that i s r e l a t i v e l y low i n vanadium might be n u t r i t i o n a l l y e i t h e r d e f i c i e n t or adequate depending on the form of the vanadium. Nonetheless, because the evidence i s i n c o n s i s t e n t , f u r t h e r s t u d i e s are necessary to d e f i n i t e l y e s t a b l i s h vanadium as an e s s e n t i a l n u t r i e n t . I t might be necessary to f i n d a s p e c i f i c p h y s i o l o g i c a l r o l e f o r vanadium i n order to e s t a b l i s h i t s essentiality. +

2

B i o l o g i c a l Function. The most recent f i n d i n g s that suggest vanadium does have a p h y s i o l o g i c a l r o l e , have come not from n u t r i t i o n a l , but from i n v i t r o s t u d i e s with (Na, K) ATPase and ATP phosphohydrolase (E.C.3.6.1.3). Although R i f k i n (46) was f i r s t to report that vanadium p o t e n t l y i n h i b i t s (Na, K)-ATPase, Cant l e y et_ a l . (47) were f i r s t to f i n d that pentavalent orthovanadate was a n a t u r a l l y o c c u r r i n g i n h i b i t o r of that enzyme. Vanadate was shown to i n h i b i t (Na, K) ATPase from kidney (46,_47,4 8), b r a i n (48) , heart (_48,_49) , red blood c e l l s (50,51), shark r e c t a l gland and e e l e l e c t r o p l a x (49). ATPphosphohydrolase from various dynein f r a c t i o n s , commonly known as dynein ATPase, a l s o was p o t e n t l y i n h i b i t e d by vanadate (52,53,54). Josephson and Cantley (55) found that vanadate d i d not p o t e n t l y i n h i b i t other ATPase systems, such as Ca-ATPase, m i t o c h o n d r i a l coupling f a c t o r F, and actomyosin. Cande and Wolniak (54) found that vanadate d i d not p o t e n t l y i n h i b i t g l y c e r i n a t e d m y o f i b r i l c o n t r a c t i o n or myosin ATPase activity. Those f i n d i n g s suggest that vanadate would be an i d e a l s p e c i f i c i n h i b i t o r of (Na, K)-ATPase or dynein ATPase. Magnesium and potassium f a c i l i t a t e vanadate i n h i b i t i o n of (Na, K)-ATPase a c t i v i t y and they both appear to bind s y n e r g i s t i c a l l y with vanadate (56). ATP depressed vanadate i n h i b i t i o n of enzyme a c t i v i t y (48). On the other hand, Gibbons L


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et a l . (53) found that dynein ATPase i n h i b i t i o n by vanadate d i d not depend upon the magnesium c o n c e n t r a t i o n or on the presence or absence of potassium. Furthermore, ATP had no obvious a f f e c t on vanadate i n h i b i t i o n of dynein ATPase. Cantley et a l . (50) found that vanadate binds to one h i g h a f f i n i t y and one low a f f i n i t y s i t e per (Na, K)-ATPase enzyme molecule. The l o w - a f f i n i t y s i t e was apparently r e s p o n s i b l e f o r i n h i b i t i o n of (Na, K)-ATPase a c t i v i t y and was the h i g h - a f f i n i t y ATP s i t e where sodium-dependent p r o t e i n phosphorylation occurs. Cantley e_t a l . (56) proposed that the unusually high a f f i n i t y of vanadate f o r (Na, K)-ATPase was due to i t s a b i l i t y to form a t r i g o n a l b i p y r a m i d a l s t r u c t u r e analogous to the t r a n s i t i o n s t a t e f o r phosphate h y d r o l y s i s . Cantley et_ a l . (50) found that vanadate was transported to the red blood c e l l where i t i n h i b i t e d the sodium pump by b i n d i n g to (Na, K)-ATPase from the cytoplasmic side (the s i t e of ATP h y d r o l y s i s ) . They suggested that the vanadium i n mammalian t i s s u e acts as a r e g u l a t o r y mechanism f o r the sodium pump that maintains a h i g h i n t r a c e l l u l a r IT to N a r a t i o by coupling w i t h ATP h y d r o l y s i s . In a d d i t i o n to a c t i n g as an i n h i b i t o r of dynein and (Na, K)-ATPase, vanadium i s a l s o a potent i n h i b i t o r of RNase (57) and a l k a l i n e and a c i d phosphatases (58,59). T h i s suggests that vanadium g e n e r a l l y tends to i n h i b i t enzymes of phosphate metabolism. However, according to Gibbons et_ a l . (53), the mechanism of i n h i b i t i o n i s not the same i n each enzyme. The i n h i b i t i o n of RNase and a l k a l i n e phosphatase i s greater by oxyvanadium (IV) than by vanadium (V). Thus, the f i n d i n g s to date suggest that vanadium has a b i o l o g i c a l f u n c t i o n i n c o n t r o l l i n g one or more enzymatic r e a c t i o n s concerned with phosphate metabolism. However, f u r t h e r i n v i v o s t u d i e s are necessary before a c o n c l u s i v e statement can be made. 1-

+

M e d i c a l S i g n i f i c a n c e . The medical s i g n i f i c a n c e of vanadium i s unclear because knowledge i s incomplete of the c o n d i t i o n s necessary to produce vanadium d e f i c i e n c y , d i e t a r y components that a f f e c t vanadium metabolism, and i t s b i o l o g i c a l f u n c t i o n . I t i s d i f f i c u l t to suggest a vanadium requirement f o r animal s p e c i e s , i n c l u d i n g humans. However, at l e a s t four independent l a b o r a t o r i e s have found that d i e t s with l e s s than 25 ng of vanadium/g adversely a f f e c t r a t s and chicks under c e r t a i n c o n d i t i o n s . I f animal data could be extrapolated to humans, then a 70 kg man consuming 1 kg of d i e t per day (dry b a s i s ) would have a d a i l y requirement of about 25 yg of vanadium under c e r t a i n d i e t a r y c o n d i t i o n s . Recent s t u d i e s have shown that the vanadium content of most foods i s very low (60,61,62,63,64), g e n e r a l l y not more than a nanogram/g. Myron et^ a l . (63) reported that nine i n s t i t u t i o n a l d i e t s s u p p l i e d 12.4-30.1 yg of vanadium d a i l y ,



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and intake averaged 20 yg. Byrne and Kosta (64) s t a t e d that the d i e t a r y intake of vanadium i s i n the order of a few tens of micrograms and may vary widely. T h i s suggests that vanadium intake i s not always optimal i n humans. In a d d i t i o n to n u t r i t i o n a l d e f i c i e n c y , n u t r i t i o n a l vanadium t o x i c i t y may have medical s i g n i f i c a n c e . The f i n d i n g s discussed p r e v i o u s l y suggest that because vanadium i s a potent i n h i b i t o r of s e v e r a l enzymes, any undue e l e v a t i o n i n t i s s u e vanadium content might adversely a f f e c t biochemical systems that depend upon normal phosphate metabolism. Even r e l a t i v e l y small amounts of d i e t a r y vanadium could be t o x i c i n some s i t u a t i o n s . For example, Hunt (65) found that the a d d i t i o n of 500 yg of chromium as the acetate/g of d i e t made 5 yg of vanadium/g of d i e t t o x i c to c h i c k s . Those chicks e x h i b i t e d depressed growth and hematocrits, elevated plasma c h o l e s t e r o l , kidney (Na, K) ATPase, and l i v e r / b o d y weight r a t i o . Morphology of t h e i r proximal t i b i a e was d r a s t i c a l l y a l t e r e d ; the growth p l a t e was abnormally t h i c k and the zone of c a l c i f i e d c a r t i l a g e abnormally t h i n . Metaphyseal bone was nonexistent. Transmission e l e c t r o n microscopic examinations revealed a disorganized growth p l a t e and the presence of an abnormal, electron-dense matrix component around the chondrocytes i n the p r o l i f e r a t i v e zone. F i v e yg of vanadium/g of d i e t without chromium supplementation had no obvious e f f e c t on c h i c k s . Cadmium, Lead, and

Tin

E s s e n t i a l i t y . At present, the evidence suggesting that cadmium, lead and t i n are e s s e n t i a l does not f u l f i l l the requirements f o r e s s e n t i a l i t y as defined by Mertz (11). Although d i e t a r y supplements of cadmium, l e a d , or t i n s l i g h t l y improved the growth of suboptimally growing r a t s , these supplements d i d not r e s u l t i n optimal growth (1,_2 >3) . Thus, i t cannot be s t a t e d unequivocally that cadmium, lead, or t i n d e f i c i e n c y r e p r o d u c i b l y r e s u l t s i n an impairment of a f u n c t i o n from optimal to suboptimal. Apparently, the suboptimal growth i n a l l r a t s i n the cadmium, lead and t i n s t u d i e s was due to r i b o f l a v i n d e f i c i e n c y (66). Unfortunately, the death of the p r i n c i p a l i n v e s t i g a t o r of cadmium, lead and t i n e s s e n t i a l i t y (Klaus Schwarz) prevented f u r t h e r s t u d i e s which would have answered the question whether d e f i c i e n c i e s of those elements would depress growth i n r a t s which were not r i b o f l a v i n - d e f i c i e n t . This question may remain unanswered f o r some time because, to my knowledge, studies concerned with the e s s e n t i a l i t y of cadmium, lead, and t i n are not c u r r e n t l y pursued i n another l a b o r a t o r y . The reports which suggest the e s s e n t i a l i t y of cadmium, lead and t i n can a l s o be c r i t i c i z e d i n the f o l l o w i n g manner: 1. The b a s a l d i e t s were not adequately described, thus preventing the confirmation of the growth f i n d i n g s i n another


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laboratory. 2. The s t a t i s t i c a l methods used f o r the a n a l y s i s of the growth data were questionable. I t was not obvious why covariance a n a l y s i s was used f o r the a n a l y s i s of t h i s type of data. Perhaps the p r e f e r a b l e a n a l y s i s of variance would have not given s i g n i f i c a n t f i n d i n g s . Furthermore, some of the s i g n i f i c a n t f i n d i n g s apparently were obtained through the method of combining experiments, thus i n c r e a s i n g the s t a t i s t i c a l term n (no. of animals) (2,3). Combining experiments before s t a t i s t i c a l treatment of the data i s i n a p p r o p r i a t e . 3. The small growth d i f f e r e n c e between " d e f i c i e n t - c o n t r o l s " and supplemented r a t s (about 5 to 7 grams a f t e r 25 to 30 days on experiment) may be of questionable p h y s i o l o g i c a l meaning. Perhaps t h i s growth response was due to the supplemental metals p a r t i a l l y preventing the breakdown of some e s s e n t i a l n u t r i e n t such as r i b o f l a v i n , or s u b s t i t u t i n g f o r some trace element l a c k i n g i n the d i e t . 4. The a d d i t i o n of suggested e s s e n t i a l metals to the d i e t was of no apparent b e n e f i t to d e f i c i e n t - c o n t r o l animals i n subsequent s t u d i e s . For example, i n the t i n s t u d i e s , the d e f i c i e n t - c o n t r o l s gained about 1.3 to 1.9 g/day; t i n supplemented r a t s , 1.7 to 2.2 g/day. However, even with the a d d i t i o n of t i n , and some other elements subsequently found p o s s i b l y e s s e n t i a l , such as f l u o r i n e and s i l i c o n , the d e f i c i e n t c o n t r o l s i n the lead study s t i l l gained only 1.5 to 2.1 g/day; lead-suppiemented r a t s , 1.6 to 2.2 g/day. D e f i c i e n t - c o n t r o l and cadmium-supplemented r a t s a l s o e x h i b i t e d s i m i l a r d a i l y weight gains. No explanation was given f o r the f i n d i n g that d e f i c i e n t - c o n t r o l s weighed the same i n each of the t i n , lead and cadmium s t u d i e s , even though one would expect the d e f i c i e n t c o n t r o l s would show b e t t e r growth rates i n l a t t e r studies because t h e i r d i e t s contained more e s s e n t i a l elements. Because of the p r e v i o u s l y discussed questions and c r i t i c i s m s , I conclude that cadmium, lead and t i n should not be included i n the l i s t of e s s e n t i a l trace metals at the present time. B i o l o g i c a l Function and M e d i c a l S i g n i f i c a n c e . U n t i l more conclusive evidence i s found suggesting cadmium, lead and t i n are e s s e n t i a l , the d e s c r i p t i o n of any p o s s i b l e b i o l o g i c a l f u n c t i o n seems i n a p p r o p r i a t e . The t o x i c o l o g i c aspects of cadmium, lead and t i n are of medical s i g n i f i c a n c e . However, a proper d i s c u s s i o n of the t o x i c o l o g y of those elements i s beyond the scope of t h i s p r e s e n t a t i o n and i s adequately done elsewhere (67,68,69). Summary The evidence to date has e s t a b l i s h e d n i c k e l as an e s s e n t i a l n u t r i e n t f o r s e v e r a l animal species. The e s s e n t i a l i t y of


2.

NIELSON

Abstruse

Trace

Metals

vanadium has not been c o n c l u s i v e l y proven. Some f i n d i n g s suggest that n i c k e l has a b i o l o g i c a l f u n c t i o n as a c o f a c t o r or s t r u c t u r a l component i n s p e c i f i c metalloenzymes or m e t a l l o p r o t e i n s , or as a b i o l i g a n d c o f a c t o r f a c i l i t a t i n g the i n t e s t i n a l absorption of the F e ( I I I ) i o n . Vanadium may f u n c t i o n as a r e g u l a t o r of some s p e c i f i c enzymes involved with phosphate metabolism. Thus, n i c k e l and vanadium might be of medical significance.


Abstract

Since 1970, a number of reports have suggested that several metals, including nickel, vanadium, cadmium, lead, and t i n , present in minute quantities in animal tissues, are essential nutrients. Findings that have indicated the essentiality of cadmium, lead, and t i n are limited, unconfirmed and of questionable physiological significance. The evidence is more substantial for the essentiality of nickel and vanadium. Also, apparent progress has been made in determining essential functions for those elements. Nickel has been shown to be an integral part of the macroglobulin nickeloplasmin isolated from human and rabbit serum, and of the enzyme urease isolated from various plants and microorganisms. Vanadium may be a regulator of (Na, K) ATPase because physiological amounts of vanadate potently inhibit that enzyme in v i t r o . In addition, important biological interactions between nickel and iron, and vanadium and chromium have been described. Thus, nickel and vanadium may also be of medical significance through their interaction with other trace metals. Literature Cited 1.

Schwarz, K . ; Spallholz, J . Growth effects of small cadmium supplements in rats maintained under trace-element controlled conditions. Fed. Proc., 1976, 35, 255.

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Nielsen, F.H.; Myron, D.R.; Givand, S.H.; Zimmerman, T.J.; Ollerich, D.A. Nickel deficiency in rats. J. Nutr., 1975, 105, 1620-1630.

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Dixon, N.E.; Gazzola, C.; Blakeley, R.L.; Zerner, B. Jack bean urease (E.C.3.5.1.5) is a metalloenzyme. A simple biological role for nickel? J. Amer. Chem. Soc., 1975, 97, 4131-4133.

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Spears, J.W.; Smith, C.J.; Hatfield, E.E. Rumen bacterial urease requirement for nickel. J. Dairy Sci., 1977, 60, 1073-1076.

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Polacco, J.C. Nitrogen metabolism in soybean tissue culture. II. Urea utilization and urease synthesis require Ni . Plant Physiol., 1977, 59, 827-830. 2+

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Gordon, W.R.; Schwemner, S.S.; Hillman, W.S. Nickel and the metabolism of urea by Lemna paucicostata Hegelm. 6746. Planta, 1978, 140, 265-268.

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Nielsen, F.H.; Zimmerman, T.J.; Collings, M.E.; Myron, D.R. Nickel deprivation in rats: Nickel-iron interactions. J. Nutr., 1979, 109, 1623-1632.

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Dowdle, E.B.; Schachter, D.; Schenker, H. Active transport of Fe by everted segments of rat duodenum. Amer. J. Physiol., 1960, 198, 609-613.


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35.

Christensen, O.B.; Möller, H. External and internal exposure to the antigen in the hand eczema of nickel allergy. Contact Dermatitis, 1975, 1, 136-141.

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Strasia, C.A. "Vanadium: Essentiality and Toxicity Laboratory Rat". Ph.D. Thesis, Purdue University, University Microfilms, Ann Arbor, MI, 1971.

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Hopkins, L.L., Jr.; Mohr, H.E. Vanadium as an essential nutrient. Fed. Proc., 1974, 33, 1773-1775.

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Hopkins, L.L., Jr.; Mohr, H.E. The biological essentiality of vanadium. In: "Newer Trace Elements in Nutrition", eds: W. Mertz and W.E. Cornatzer. Marcel Dekker, Inc., New York, NY, 1971, pp. 195-213.

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Hopkins, L.L., Jr.; Mohr, H.E. Effect of vanadium deficiency on plasma cholesterol of chicks. Fed. Proc., 1971, 30, 462.

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in the

essentiality of arsenic, possible nutritional Nutritional Research", ed: Corp., New York, NY, 1979,



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45.

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46.

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Cantley, L.C., Jr.; Josephson, L.; Warner, R.; Yanagisawa, M.; Lechene, C.; Guidotti, G. Vanadate is a potent (Na, K)ATPase inhibitor found in ATP derived from muscle. J. Biol. Chem., 1977, 252, 7421-7423.

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49.

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RECEIVED May 21,

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