Enhanced Tissue Lipid Peroxidation - ACS ... - ACS Publications

Chapter 6

Enhanced Tissue Lipid Peroxidation Mechanism Underlying Pathologies Associated with Dietary Manganese Deficiency Sheri

Zidenberg-Cherr

1,2

and C a r l L. Keen

1,3

Department of Nutrition, University of California—Davis, Davis, CA 95616 Laboratory for Energy-Related Health Research, University of California—Davis, Davis, CA 95616 Department of Internal Medicine, University of California—Davis, Davis, CA 95616 1

2

Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: October 5, 1987 | doi: 10.1021/bk-1987-0354.ch006

3

While i t is recognized that a deficiency of Mn has pathological consequences, the underlying biochemical lesions have not been defined. One hypothesis is that Mn deficiency results in a reduction in Mn superoxide dismutase (MnSOD) activity with a subsequent increase in tissue lipid peroxidation and cellular damage. In support of this idea, Mn-deficient animals are characterized by low liver MnSOD activity and high levels of liver mitochondrial lipid peroxidation. Ultrastructural studies showing mitochondrial membrane abnormalities in liver from Mn-deficient rats support the hypothesis that increased tissue lipid peroxidation results in cellular damage. Based on the above i t can be speculated that Mn deficiency should increase the cytotoxicity of environmental insults which increase the production of superoxide ion radical. Consistent with this idea is evidence that the metabolism of, and the physiological response to, a number of free radical inducers is affected by Mn status. The essentiality of manganese (Mn) for animals was established in 1931 by Orent and McCollum (1) who reported that this element is required for normal reproduction in the rat, and Kemmerer and colleagues (2) who showed that it was necessary for normal growth and reproduction in the mouse. Since then several investigators have verified the critical need of this nutrient for normal development (3). Manifestations of perinatal Mn deficiency in experimental animals include neonatal death, impaired growth, skeletal abnormalities, depressed reproductive function, congenital ataxia, and defects in protein, carbohydrate and lipid metabolism. Although it is evident that Mn is needed for several biological functions, its precise biochemical roles have not been delineated. Manganese is involved in numerous biochemical reactions both as an integral part of metalloenzymes and as an enzyme activator. 0097-6156/87/0354-0056$06.00/0 © 1987 American Chemical Society

Kies; Nutritional Bioavailability of Manganese ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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A l t h o u g h t h e r e a r e numerous enzymes known t o be a c t i v a t e d by Mn, few Mn metalloenzymes have been r e c o g n i z e d . With the exception o f t h e g l y c o s y l t r a n s f e r a s e enzymes, t h e enzymes f o r which Mn i s a c o f a c t o r are u s u a l l y non-sjj>ecifically a c t i v a t e d , with other d i v a l e n t c a t i o n s such as Mg b e i n g a b l e t o t a k e t h e p l a c e o f Mn (4,5). Enzymes which c o n t a i n Mn i n c l u d e p y r u v a t e c a r b o x y l a s e , a r g i nase, and s u p e r o x i d e d i s m u t a s e . T h i s p a p e r w i l l f o c u s on t h e r o l e o f Mn as a component o f Mn s u p e r o x i d e d i s m u t a s e (MnSOD) and t h e f u n c t i o n a l s i g n i f i c a n c e o f a l t e r a t i o n s i n the a c t i v i t y of t h i s enzyme. +


F u n c t i o n o f Manganese S u p e r o x i d e Dismutase

(MnSOD)

The m a j o r i t y o f t h e O^ reduced by a e r o b i c c e l l s i s c a r r i e d o u t t h r o u g h t h e 4 e l e c t r o n r e d u c t i o n s by cytochrome o x i d a s e ( 6 ) , t h u s p r e v e n t i n g t h e r e l e a s e o f e x c e s s i v e amounts o f r e a c t i v e i n t e r m e d i a t e s such as 0 " , ^2°2 * * ' s m a l l amounts o f these r e a c t i v e intermediates are generated during the r e d u c t i o n o f 0 t o H 0 ( 7 ) . In a d d i t i o n t o t h e r e d u c t i o n o f 0 i n t h e e l e c t r o n t r a n s p o r t c h a i n , t h e a c t i v i t y o f a group o f c e l l u l a r enzymes which are i n v o l v e d i n c a t a l y z i n g o x i d a t i o n r e a c t i o n s r e s u l t s i n u n i v a l e n t r e d u c t i o n o f 0 t o 0 ' . These i n c l u d e x a n t h i n e o x i d a s e and p e r o x idases. As many o f t h e s e enzymes a r e l o c a t e d i n t h e m i t o c h o n d r i a , t h e s e o r g a n e l l e s can c o n t r i b u t e s u b s t a n t i a l amounts o f 0^' . I n a d d i t i o n , t h e a u t o x i d a t i o n o f a l a r g e group o f compounds a l s o c o n t r i b u t e s t o t h e O^" c o n c e n t r a t i o n i n l i v i n g systems. These i n c l u d e c a t e c h o l a m i n e s , f l a v i n s and f e r r e d o x i n ( 8 ) . The 0 f l u x i n a e r o b i c c e l l s appears t o have n e c e s s i t a t e d t h e development o f SOD's w h i c h c a t a l y z e t h e d i s m u t a t i o n o f 0 to H 0 + 0 » Two t y p e s o f SOD's have been d e s c r i b e d i n mammalian c e l l s . One c o n t a i n s Mn and i s l o c a l i z e d p r i m a r i l y i n t h e m i t o c h o n d r i a . The o t h e r c o n t a i n s Cu and Zn and i s found p r i m a r i l y i n t h e c y t o s o l . Manganese s u p e r o x i d e d i s m u t a s e i s o l a t e d from c h i c k e n , r a t and human l i v e r has a m o l e c u l a r w e i g h t o f 80,000 and c o n t a i n s 4 s u b u n i t s o f e q u a l s i z e , each c o n t a i n i n g one atom o f Mn ( 9 ) . I n c o n t r a s t t o p y r u v a t e c a r b o x y l a s e and a r g i n a s e , t h e Mn i n r e s t i n g SOD i s i n t h e t r i v a l e n t s t a t e . The c a t a l y t i c c y c l e o f t h i s enzyme i n v o l v e s r e d u c t i o n and t h e n r e o x i d a t i o n o f t h e m e t a l c e n t e r d u r i n g s u c c e s s i v e e n c o u n t e r s w i t h oxygen. L i k e o t h e r enzymes o f t h e m i t o c h o n d r i a which a r e s y n t h e s i z e d i n t h e c y t o p l a s m , MnSOD i s s y n t h e s i z e d i n i t i a l l y as a h i g h e r m o l e c u l a r w e i g h t p r e c u r s o r p o l y p e p t i d e . F i n a l p r o c e s s i n g t o t h e mature form presumably o c c u r s i n t h e m i t o chondria. The h i g h c o n c e n t r a t i o n o f p o l y u n s a t u r a t e d f a t t y a c i d s i n c e l l u l a r and s u b c e l l u l a r membranes makes them p a r t i c u l a r l y s u s c e p t i b l e t o f r e e r a d i c a l damage. I n a d d i t i o n , m i t o c h o n d r i a l membranes c o n t a i n f l a v i n s as a p a r t o f t h e i r b a s i c s t r u c t u r e , p o t e n t i a l l y contributing 0 r e s u l t i n g i n f r e e r a d i c a l damage. The p r o c e s s o f u n c o n t r o l l e d l i p i d p e r o x i d a t i o n can r e s u l t i n t h e l o s s o f e s s e n t i a l p o l y u n s a t u r a t e d f a t t y a c i d s , and t h e f o r m a t i o n o f t o x i c h y d r o p e r o x i d e s and o t h e r s e c o n d a r y p r o d u c t s . The l o s s o f e s s e n t i a l f a t t y a c i d s may t h e n r e s u l t i n l o s s o f membrane i n t e g r i t y and l o s s o f function. E x t e n s i v e o x i d a t i o n can a l s o l e a d t o r u p t u r e o f a

n

d

0 H

H

o

w

e

v

e

r

2

2

2

2

#

2

2

2


2

2

58

NUTRITIONAL

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O F MANGANESE

s u b c e l l u l a r membranes w i t h subsequent r e l e a s e o f l y s o s o m a l and i r r e v e r s i b l e damage t o t h e c e l l (10).

enzymes,


I n f l u e n c e o f D i e t a r y Manganese on MnSOD A c t i v i t y A d i e t a r y d e f i c i e n c y o f Mn h a s been shown t o r e s u l t i n a r e d u c t i o n o f MnSOD a c t i v i t y i n r a t s , mice, and c h i c k e n s . I n a d u l t mice f e d d i e t s d e f i c i e n t i n Mn (1 ug Mn/g d i e t ) p r e n a t a l l y and p o s t n a t a l l y , the a c t i v i t y o f t h i s enzyme was s i g n i f i c a n t l y lower i n l i v e r , b r a i n , h e a r t , and l u n g than i n t i s s u e s o f a n i m a l s f e d c o n t r o l d i e t s (45 ug Mn/g d i e t ) (11) . I n c h i c k e n s , t h e r e was lower a c t i v i t y o f MnSOD i n l i v e r a f t e r o n l y 7 days o f f e e d i n g a M n - d e f i c i e n t d i e t (1 ug Mn/g d i e t ) t o h a t c h l i n g s compared t o c o n t r o l s . The a c t i v i t y o f t h e enzyme was q u i c k l y e l e v a t e d t o normal by t h e f e e d i n g o f Mnadequate d i e t s . C o n c o m i t a n t w i t h t h e d e c l i n e i n a c t i v i t y o f MnSOD, t h e a c t i v i t y o f c o p p e r - z i n c SOD (CuZnSOD) was i n c r e a s e d , s u g g e s t i n g a compensatory r e s p o n s e t o O^ which was n o t d i s m u t a t e d due t o t h e lower MnSOD a c t i v i t y . P a y n t e r (12) h a s r e p o r t e d t h a t a r e d u c t i o n i n h e a r t and k i d n e y MnSOD c a n a l s o o c c u r i n r a t s when t h e d e f i c i e n t d i e t s a r e i n i t i a t e d a t weaning. F u n c t i o n a l S i g n i f i c a n c e o f Low MnSOD A c t i v i t y While t h e above shows t h a t t h e a c t i v i t y o f t h e enzyme c a n be a f f e c t e d by d i e t a r y Mn i n t a k e , i t i s i m p o r t a n t t o d e t e r m i n e i f t h i s reduction i n a c t i v i t y i sof physiological significance. An e x c e l l e n t model t o study t h i s q u e s t i o n i s t h e neonate. B i r t h and weaning a r e c r i t i c a l p e r i o d s i n t h e l i f e o f a mammal; b o t h a r e a s s o c i a t e d w i t h s e v e r a l pronounced enzyme changes. Immediately a f t e r b i r t h , t h e neonate must depend on i t s g l y c o g e n r e s e r v e s f o r a continuous supply o f glucose. L a t e r , g l u c o n e o g e n i c enzymes emerge, and t h e a n i m a l i s c a p a b l e o f s y n t h e s i z i n g g l u c o s e from g l y c o l y t i c p r o d u c t s and amino a c i d s (13) . There i s an i n c r e a s e i n o x i d a t i v e m e t a b o l i s m d u r i n g t h i s p e r i o d ; thus an i n c r e a s e i n t h e p r o d u c t i o n o f O* and i n c r e a s e d a c t i v i t y o f SOD might be e x p e c t e d , i n o r d e r t o combat i t s e l e v a t e d p r o d u c t i o n . Consistent with t h i s idea are the f i n d i n g s by Y o s h i o k a e t a l . (14) who r e p o r t e d t h a t SOD a c t i v i t y was a t i t s l o w e s t l e v e l d u r i n g t h e f e t a l p e r i o d t h r o u g h day 5 o f p o s t n a t a l development i n t h e r a t . There was a r a p i d r i s e i n a c t i v i t y from day 10 t h r o u g h day 20, r e a c h i n g l e v e l s t h a t were 88% o f t h o s e o b s e r v e d i n a d u l t s . S i m i l a r r e s u l t s were r e p o r t e d by L a n k i n and c o l l e a g u e s (15) and M a v e l l i e t a l . (16). I f the Mn-deficient a n i m a l i s u n a b l e t o m a i n t a i n an adequate l e v e l o f e n z y m a t i c p r o t e c t i o n a g a i n s t o x y g e n - d e r i v e d r a d i c a l s , d e t r i m e n t a l consequences may occur. F o r example, t h i s may e x p l a i n t h e h i g h i n c i d e n c e o f neon a t a l m o r t a l i t y observed i n the M n - d e f i c i e n t animal. To t e s t t h i s i d e a , we examined t h e changes t h a t o c c u r from b i r t h t o m a t u r i t y (d 60) i n t h e a c t i v i t y o f MnSOD and CuZnSOD i n s e v e r a l t i s s u e s o f M n - s u f f i c i e n t and - d e f i c i e n t mice. In t h i s s t u d y , t i s s u e Mn c o n c e n t r a t i o n s i n c r e a s e d w i t h age i n b o t h groups; however, t h e i m p o s i t i o n o f a d i e t a r y Mn d e f i c i e n c y r e s u l t e d i n l o w e r than normal l e v e l s o f Mn by day 60 i n a l l t i s s u e s examined. The d e v e l o p m e n t a l p a t t e r n o f MnSOD a c t i v i t y p a r a l l e l e d t h a t f o r Mn c o n c e n t r a t i o n (17).



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L i v e r and k i d n e y c o n t a i n e d t h e g r e a t e s t amount o f MnSOD a c t i v i t y i n mice, a p p r o x i m a t e l y 30% more t h a n b r a i n and h e a r t . I n the mature a n i m a l , Mn d e f i c i e n c y a f f e c t e d MnSOD a c t i v i t y most d r a m a t i c a l l y i n t h e l i v e r , w i t h s m a l l e r changes i n k i d n e y and h e a r t , and a l m o s t no change i n t h e b r a i n . An i n t r i g u i n g o b s e r v a t i o n i s t h a t MnSOD a c t i v i t y was r e t a i n e d even w i t h t h e v e r y low amounts o f t i s s u e Mn i n d e f i c i e n t a n i m a l s . These f i n d i n g s s u g g e s t t h e importance o f e n z y m a t i c p r o t e c t i o n a g a i n s t f r e e r a d i c a l damage. I t i s i n t e r e s t i n g t h a t normal l e v e l s o f MnSOD were m a i n t a i n e d i n b r a i n s from M n - d e f i c i e n t mice; we have l i m i t e d d a t a t h a t i n d i c a t e t h a t Mn c o n c e n t r a t i o n i s lower t h a n normal i n b r a i n s from M n - d e f i c i e n t mice. Perhaps o t h e r r o l e s o f Mn i n t h i s t i s s u e a r e b e i n g compromised i n o r d e r t o p r o v i d e adequate MnSOD a c t i v i t y . To a s s e s s t h e f u n c t i o n a l s i g n i f i c a n c e o f lower t h a n normal a c t i v i t y o f MnSOD, we measured h e p a t i c l i p i d p e r o x i d a t i o n and MnSOD a c t i v i t y i n M n - s u f f i c i e n t and - d e f i c i e n t r a t s . I n t h e s e s t u d i e s we used r a t s i n o r d e r t o i n c r e a s e t h e amount o f t i s s u e a v a i l a b l e f o r the l i p i d p e r o x i d a t i o n s t u d i e s . S i m i l a r t o t h e f i n d i n g s i n mice, a c t i v i t y o f l i v e r MnSOD i n c r e a s e d from b i r t h t h r o u g h 60 days o f age. By day 60, MnSOD a c t i v i t y i n M n - d e f i c i e n t r a t s was h a l f t h a t observed i n M n - s u f f i c i e n t r a t s (Figure 1). That t h i s d i f f e r e n c e i n SOD a c t i v i t y i s o f s i g n i f i c a n c e i s s u g g e s t e d by t h e o b s e r v a t i o n t h a t a t day 60, m i t o c h o n d r i a l l i p i d p e r o x i d a t i o n i n M n - d e f i c i e n t r a t s , as a s s e s s e d by m e a s u r i n g TBA r e a c t i n g p r o d u c t s , was 3 t i m e s t h a t o b s e r v e d i n M n - s u f f i c i e n t r a t s ( F i g u r e 2) (18). These f i n d i n g s s u g g e s t e d t h a t t h e damage t o m i t o c h o n d r i a l membranes p r e v i o u s l y o b s e r v e d i n M n - d e f i c i e n t a n i m a l s (1) was due i n p a r t t o d e p r e s s e d MnSOD a c t i v i t y which r e s u l t e d i n i n c r e a s e d l i p i d p e r o x i d a t i o n from f r e e r a d i c a l s . To i n v e s t i g a t e t h i s p o s s i b i l i t y t h e e f f e c t s o f Mn d e f i c i e n c y d u r i n g p r e n a t a l and p o s t n a t a l development on m i t o c h o n d r i a l s t r u c t u r e i n t h e r a t were a s s e s s e d . Despite s i g n i f i c a n t d i f f e r e n c e i n MnSOD a c t i v i t y , l i v e r s from M n - s u f f i c i e n t and - d e f i c i e n t r a t s from day 3 t o day 60 e x h i b i t e d normal u l t r a s t r u c t u r e (19). However, a t 9 months o f age, l i v e r from t h r e e o f the f o u r M n - d e f i c i e n t r a t s showed abnormal m i t o c h o n d r i a , whereas t h o s e o f c o n t r o l r a t s had normal u l t r a s t r u c t u r e . I n t h e d e f i c i e n t a n i m a l s , l a r g e v a c u o l e s were p r e s e n t i n t h e m a t r i x o f many m i t o chondria. The i n n e r and o u t e r m i t o c h o n d r i a l membranes were separ a t e d from each o t h e r , c r e a t i n g open s p a c e s . Similar abnormalities have been o b s e r v e d i n l i v e r from p a t i e n t s w i t h W i l s o n ' s d i s e a s e (20), d i s e a s e s o f m i t o c h o n d r i a l myopathy (21) , and A d r i a m y c i n t r e a t m e n t (22). The u n d e r l y i n g mechanisms o f t h e s e changes a r e unknown; however, e x c e s s i v e l i p i d p e r o x i d a t i o n h a s been s u g g e s t e d as a c o n t r i b u t i n g f a c t o r . We s u g g e s t t h a t t h e m i t o c h o n d r i a l a b n o r m a l i t i e s o b s e r v e d i n t h e 9 month o l d M n - d e f i c i e n t r a t s a r e a t l e a s t i n p a r t t h e r e s u l t o f t h e lower MnSOD a c t i v i t y o c c u r r i n g a t 60 days o f age accompanied by e x c e s s i v e m i t o c h o n d r i a l l i p i d p e r o x i dation. S i n c e no s t r u c t u r a l a b n o r m a l i t i e s were a p p a r e n t e a r l i e r , t h e r e s u l t i n g m i t o c h o n d r i a l damage o b s e r v e d i n t h i s study may have r e s u l t e d from numerous f a c t o r s c o n t r i b u t i n g t o s t r u c t u r a l damage over a p e r i o d o f time. F o r example, l i p i d c o m p o s i t i o n o f t h e membrane may have been a l t e r e d due t o e l e v a t e d l i p i d p e r o x i d a t i o n . A d d i t i o n a l l y , Mn i s a c o f a c t o r f o r s e v e r a l enzymes f u n c t i o n i n g i n


NUTRITIONAL BIOAVAILABILITY O F MANGANESE


0 I 0

i I

i i i ' \\' ' ' ' i i i 2 3 4 5 10 20 30 40 50 60 70 AGE (days)

F i g u r e 1. A g e - r e l a t e d changes i n r a t l i v e r MnSOD a c t i v i t y f o r Mn-sufficient ( ) and - d e f i c i e n t ( - - - ) r a t s . Values shown a r e u n i t s / g l i v e r wet w e i g h t . E a c h p o i n t r e p r e s e n t s t h e mean o f a t l e a s t t h r e e r a t s .

700

r

oI

' I

' 2

' 3

' 4

t> i i i i i i | 5 10 20 30 4 0 50 60 7 0 AGE (days) x

F i g u r e 2. L i p i d p e r o x i d a t i o n as measured by TBA r e a c t i n g p r o d u c t s (absorbance a t 532 nm) i n l i v e r m i t o c h o n d r i a f o r Mn-sufficient ( ) and - d e f i c i e n t ( - - - ) r a t s . Isolated m i t o c h o n d r i a were i n c u b a t e d i n T r i s - H C l b u f f e r , pH 7 . 4 , w i t h t h e a d d i t i o n o f oxygen i n i t i a t o r s . Each p o i n t r e p r e s e n t s t h e mean of a t l e a s t three r a t s .


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c h o l e s t e r o l s y n t h e s i s and f a t t y a c i d s y n t h e s i s ; t h u s a l t e r a t i o n s i n t h e s y n t h e s i s o f t h e s e compounds c o u l d c o n t r i b u t e t o abnormal membranes ( 1 ) .


Influence Inducers

o f Manganese D e f i c i e n c y on Response t o F r e e

Radical

In a d d i t i o n t o d i e t , t h e a c t i v i t y o f MnSOD can be i n d u c e d under c o n d i t i o n s which r e s u l t i n an i n c r e a s e d p r o d u c t i o n o f 0* s u c h as e x p o s u r e t o h y p e r b a r i c oxygen. H y p e r o x i a i n d u c e s b o t h MnSOD and c a t a l a s e a c t i v i t y i n pulmonary macrophages whether t h e c e l l s a r e i n c u b a t e d i n v i t r o o r i f t h e a n i m a l s a r e exposed i n v i v o (23) . S i m i l a r l y , ozone (0 ) i n h a l a t i o n has been shown t o i n c r e a s e t o t a l l u n g CuZnSOD and MnSOD a c t i v i t y i n mice (24). Taken t o g e t h e r t h e s e f i n d i n g s s u g g e s t t h a t an a n i m a l w i t h an i n a d e q u a t e d e f e n s e system such as low MnSOD a c t i v i t y may be more s u s c e p t i b l e t o t h e d e l e t e r i o u s consequences o f such a g e n t s . To a s s e s s t h e i n f l u e n c e o f Mn s t a t u s on t h e r e s p o n s e t o ozone exposure, M n - s u f f i c i e n t and - d e f i c i e n t mice were exposed t o O^ (1.21 ± 0.02 ppm) o r f i l t e r e d a i r f o r 7 days (25). R e g a r d l e s s o f d i e t a r y t r e a t m e n t , O^ exposure r e s u l t e d i n an i n c r e a s e i n l u n g wet w e i g h t (Table I ) . TABLE I . E f f e c t o f Ozone Exposure on Mouse Body and Lung Weight, and Lung SOD A c t i v i t y Body wt (g) Mn-adequate Air Ozone Mn-deficient Air Ozone

Lung wt (g)

CuZnSOD

MnSOD

(u/

(u/

(u/

g lung)

lung)

g lung)

(u/ lung)

25. .8±2, .4 26. ,7±0, .86

0.,17±0..01 0.,22±0..02

230±10 190± 8

40±4 60±2

120±5 90±3

25±3 30±3

30. .2±2, .6 31. .1±1, .7

0,,22±0..02 0..35±0..02

230±10 220± 8

50±5 75±2

115±5 50±4

28±3 28±3

T h i s i n c r e a s e r e f l e c t s t h e edematous and i n f l a m m a t o r y r e s p o n s e o f t h e l u n g t o O e x p o s u r e . N e i t h e r l u n g CuZnSOD n o r MnSOD a c t i v i t y was a f f e c t e d by d i e t i n a i r - b r e a t h i n g g r o u p s . I n marked c o n t r a s t , exposure t o O r e s u l t e d i n an i n c r e a s e i n t o t a l l u n g SOD a c t i v i t y i n t h e M n - s u f f i c i e n t group; t h i s i n c r e a s e was a f u n c t i o n o f h i g h e r a c t i v i t i e s o f b o t h MnSOD and CuZnSOD i n t h e s e a n i m a l s . Exposure t o O^ a l s o r e s u l t e d i n an i n c r e a s e i n t o t a l SOD a c t i v i t y i n Mnd e f i c i e n t mice; however, i n t h e s e a n i m a l s t h e i n c r e a s e o c c u r r e d as a r e s u l t o f a s e l e c t i v e i n c r e a s e i n CuZnSOD a c t i v i t y . These r e s u l t s show t h a t t h e t y p i c a l i n c r e a s e i n MnSOD a c t i v i t y i n r e s p o n s e t o O exposure i s i m p a i r e d by d i e t a r y Mn d e f i c i e n c y . The o b s e r v a t i o n t h a t t h e r e was a compensatory i n c r e a s e i n t h e a c t i v i t y o f CuZnSOD i n t h e M n - d e f i c i e n t mice exposed t o O^ s u g g e s t s t h a t t h e i n c r e a s e i n t h e a c t i v i t i e s o f t h i s enzyme i s i n p a r t s u b s t r a t e - i n d u c e d , and s t r o n g l y s u p p o r t s t h e h y p o t h e s i s t h a t t h e i n c r e a s e i n l u n g SOD a c t i v i t y i s an i m p o r t a n t r e s p o n s e t o 0 e x p o s u r e . Thus i f t h e n e t i n c r e a s e i n l u n g SOD a c t i v i t y i s l i m i t e d by t h e n u t r i t i o n a l s t a t u s o f t h e a n i m a l , t h e n e x c e s s i v e l u n g damage may o c c u r due t o f r e e r a d i c a l - i n i t i a t e d p e r o x i d a t i o n s . 3



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S i m i l a r t o 0 , a l c o h o l i s t h o u g h t t o e x e r t some o f i t s t o x i c e f f e c t s t h r o u g h t h e p r o d u c t i o n o f 0^ d u r i n g i t s m e t a b o l i s m . Cons i s t e n t with t h i s theory i s the observation that a l c o h o l feeding can r e s u l t i n i n c r e a s e d SOD a c t i v i t y . I n r a t s (26) and p r i m a t e s (27) e t h a n o l consumption r e s u l t e d i n i n c r e a s e d MnSOD a c t i v i t y . In c o n t r a s t t o i n c r e a s e d MnSOD a c t i v i t y , d e c r e a s e s i n l i v e r CuZnSOD a c t i v i t y were found w i t h c h r o n i c e t h a n o l f e e d i n g i n r a t s and p r i m a t e s . A c u t e l o a d s o f e t h a n o l f e e d i n g have a l s o been r e p o r t e d t o a f f e c t SOD l e v e l s . Mandal and co-workers (28) found t h a t b r a i n SOD l e v e l s were d e c r e a s e d i n r a t s f o l l o w i n g acute e t h a n o l f e e d i n g , and have s u g g e s t e d t h a t some o f t h e e f f e c t s o f e t h a n o l on t h e nervous system a r e due t o t h e c y t o t o x i c e f f e c t s o f superoxide r a d i c a l s . I n c o n t r a s t , V a l e n z u e l a and co-workers (29) r e p o r t e d an i n c r e a s e i n l i v e r SOD l e v e l s i n r a t s g i v e n an a c u t e feeding of ethanol. The d i f f e r e n c e between t h e r e s u l t s o f Mandal and co-workers and V a l e n z u e l a and co-workers may be due t o d i f f e r ences i n t h e d i e t a r y s t a t u s o f t h e i r a n i m a l s , t i s s u e s p e c i f i c i t y , o r t h e time sequence o f t h e i n s u l t s . The above s u g g e s t s t h a t t h e i n c r e a s e i n t i s s u e MnSOD a c t i v i t y w i t h e t h a n o l _ c o n s u m p t i o n r e f l e c t s a compensatory r e a c t i o n t o t h e i n c r e a s e d 0* l o a d . T h e r e f o r e t h e a b i l i t y o f t h e a n i m a l t o i n c r e a s e t h e amount o f t h i s enzyme may d i c t a t e t h e e x t e n t o f t h e p a t h o l o g y which c o u l d o c c u r due t o t h i s i n s u l t . To t e s t t h i s h y p o t h e s i s , M n - s u f f i c i e n t and - d e f i c i e n t r a t s were g i v e n e i t h e r 20% (w/v) e t h a n o l o r d e i o n i z e d water as t h e i r d r i n k i n g f l u i d (30). There was no d i f f e r e n c e i n d a i l y c a l o r i c i n t a k e between t h e Mns u f f i c i e n t and - d e f i c i e n t r a t s n o t r e c e i v i n g e t h a n o l . Both groups consumed a p p r o x i m a t e l y 15 g o f p u r i f i e d d i e t a day, which i s e q u i v a l e n t t o about 68 k c a l o f m e t a b o l i z a b l e energy p e r day. From days 2-6, t h e d a i l y c a l o r i c i n t a k e o f t h e e t h a n o l - f e d r a t s d e c r e a s e d t o 76 and 42% o f t h a t found i n t h e r a t s n o t f e d e t h a n o l f o r M n - s u f f i c i e n t and - d e f i c i e n t r a t s , r e s p e c t i v e l y . E t h a n o l - f e d r a t s were consuming 50% o f t h e i r c a l o r i e s from e t h a n o l and 50% from the d i e t . A f t e r day 6, t h e e t h a n o l - f e d M n - s u f f i c i e n t r a t s i n c r e a s e d t h e i r c a l o r i c i n t a k e above t h a t o f t h e r a t s n o t f e d e t h a n o l by e a t i n g more f o o d and by d r i n k i n g more e t h a n o l than d u r i n g t h e f i r s t 6 d a y s . T h e i r c a l o r i c i n t a k e d u r i n g t h i s p e r i o d a v e r a g e d 90 k c a l / d a y , 50% from e t h a n o l and 50% from d i e t . In contrast, the e t h a n o l - f e d M n - d e f i c i e n t r a t s c o n t i n u e d t o consume an average o f 30 k c a l / d a y , 65% from e t h a n o l and 35% from t h e i r f o o d . The body w e i g h t changes o f t h e r a t s d u r i n g t h i s time were c o n s i s t e n t w i t h t h e i r c a l o r i c i n t a k e . D u r i n g t h e f i r s t week o f e t h a n o l f e e d i n g , M n - s u f f i c i e n t r a t s l o s t 15% o f t h e i r i n i t i a l body weight. However, d u r i n g week 2 t h e s e r a t s g a i n e d an average o f 9 g, which b r o u g h t them t o about 90% o f t h e i r i n i t i a l body w e i g h t . In c o n t r a s t , t h e e t h a n o l - f e d M n - d e f i c i e n t r a t s l o s t 20% o f t h e i r i n i t i a l body w e i g h t d u r i n g week 1 and c o n t i n u e d t o l o s e w e i g h t d u r i n g week 2. A f t e r 14 days o f e t h a n o l f e e d i n g , t h e e t h a n o l - f e d M n - d e f i c i e n t r a t s were e x t r e m e l y l e t h a r g i c and i n p o o r c o n d i t i o n , w i t h pigment e n c r u s t a t i o n o f t h e f a c i a l and neck r e g i o n . A f t e r 14 days t h e body w e i g h t o f t h i s group o f r a t s was o n l y 65% o f t h e i n i t i a l w e i g h t . The consumption o f e t h a n o l by M n - d e f i c i e n t r a t s r e s u l t e d i n a t r e n d toward h i g h e r l e v e l s o f l i v e r Mn and l i v e r MnSOD a c t i v i t y t h a n t h o s e o b s e r v e d i n d e f i c i e n t r a t s t h a t were n o t



6.

ZIDENBERG-CHERR AND KEEN

Enhanced

Tissue

Lipid

Peroxidation

63

f e d e t h a n o l . However, t h e s e f i n d i n g s may be due t o t h e f a c t t h a t l i v e r s i z e had d e c r e a s e d i n t h i s group. This finding i s consistent w i t h t h o s e o f Barak e t a l . (31) who o b s e r v e d t h a t a l c o h o l i n c r e a s e s t h e l e v e l o f h e p a t i c Mn i n normal r a t s , and D r e o s t i e t a l . ( 2 6 ) , who r e p o r t e d an i n c r e a s e i n c y a n i d e - i n s e n s i t i v e SOD a c t i v i t y a f t e r e t h a n o l consumption i n normal r a t s . Based on t h e l a c k o f s i g n i f i c a n t d i f f e r e n c e s among t h e f o u r groups w i t h r e g a r d t o MnSOD a c t i v i t y i t i s u n l i k e l y t h a t t h e t o x i c i t y p r o d u c e d by e t h a n o l i n M n - d e f i c i e n t r a t s was due s i m p l y t o i n a d e q u a t e l e v e l s o f MnSOD, b u t r a t h e r r e p r e s e n t s an o v e r a l l d i m i n i s h e d a b i l i t y o f t h e d e f i c i e n t animal t o respond t o t h i s p a r t i c u l a r agent. Another agent which we have used t o e v a l u a t e t h e i n f l u e n c e o f Mn on s u p e r o x i d e m e t a b o l i s m i s t h e a n t i b i o t i c A d r i a m y c i n (ADR). A d r i a m y c i n i s c o n s i d e r e d one o f t h e most p o t e n t drugs i n t h e f i e l d o f chemotherapy, y e t i t s c l i n i c a l u s e f u l n e s s i s compromised by a number o f s e r i o u s s i d e e f f e c t s i n c l u d i n g a dose-dependent c a r d i o toxicity. A d r i a m y c i n - i n d u c e d h e a r t d i s e a s e i s c h a r a c t e r i z e d by d e g e n e r a t i o n o f t h e c a r d i a c muscle; m i t o c h o n d r i a a r e e n l a r g e d and t h e i n t r a c r i s t a l spaces a r e s u b s t a n t i a l l y extended. We have e v a l u a t e d t h e b i o c h e m i c a l r e s p o n s e o f mice t o ADR t r e a t m e n t when f e d e i t h e r M n - s u f f i c i e n t o r - d e f i c i e n t d i e t s . I n a d d i t i o n we v a r i e d t h e l e v e l o f v i t a m i n E t o a s s e s s t h e i n f l u e n c e o f a combined d e f i c i t o f d i e t a r y a n t i o x i d a n t s on ADR t o x i c i t y ( 3 3 ) . A d r i a m y c i n i n j e c t i o n had no e f f e c t on l i v e r Mn c o n c e n t r a t i o n . I n c o n t r a s t , l i v e r Fe c o n c e n t r a t i o n was i n f l u e n c e d by b o t h d i e t and ADR i n j e c t i o n . A l t h o u g h t h e r e was a t r e n d towards h i g h e r t h a n normal c o n c e n t r a t i o n s o f l i v e r Fe i n a l l groups t r e a t e d w i t h ADR, o n l y t h o s e a n i m a l s f e d d i e t s low i n b o t h a n t i o x i d a n t s had s i g n i f i c a n t l y h i g h e r l e v e l s (254.8 ± 72 ug Fe/g l i v e r ) t h a n t h e i r s a l i n e i n j e c t e d c o n t r o l s (140.7 ± 44 ug Fe/g l i v e r ) . H e a r t MnSOD a c t i v i t y i n t h e M n - d e f i c i e n t mice was a p p r o x i m a t e l y 50% t h a t o f M n - s u f f i c i e n t mice. A d r i a m y c i n i n j e c t i o n h a d no e f f e c t on h e a r t MnSOD a c t i v i t y . The TBA i n d e x was h i g h e s t i n t h o s e a n i m a l s f e d d i e t s low i n v i t a m i n E and Mn; v a l u e s f o r t h i s group were a p p r o x i m a t e l y 2 - f o l d h i g h e r t h a n t h o s e o b s e r v e d i n a n i m a l s f e d d i e t s which were n u t r i t i o n a l l y complete. A d r i a m y c i n d i d n o t i n f l u e n c e t h e TBA i n d e x i n any d i e t a r y group. R e s u l t s from t h i s s t u d y showed t h a t SOD a c t i v i t y was n o t a f f e c t e d by a c u t e ADR t r e a t m e n t . A second f i n d i n g was t h a t a c u t e ADR t o x i c i t y d i d n o t promote c a r d i a c l i p i d p e r o x i d a t i o n . However, i t was o b s e r v e d t h a t m i t o c h o n d r i a l l i p i d p e r o x i d a t i o n was h i g h e s t i n mice f e d d i e t s low i n b o t h a n t i o x i d a n t s . Ultrastructural examination r e v e a l e d m i t o c h o n d r i a l a b n o r m a l i t i e s i n c a r d i a c t i s s u e from A D R - t r e a t e d a n i m a l s ( F i g u r e s 3 and 4 ) . There were l a r g e v a c u o l e s w i t h i n t h e m i t o c h o n d r i a and c o n d e n s a t i o n o f t h e i n n e r and o u t e r membranes o f t h e m i t o c h o n d r i a . The u l t r a s t r u c t u r a l e f f e c t s o f ADR t r e a t m e n t were most s e v e r e i n t h e low E , M n - d e f i c i e n t m i c e . I t i s r e a s o n a b l e t o s u g g e s t t h a t a h i g h e r t h a n normal l e v e l o f l i p i d p e r o x i d a t i o n may p r e d i s p o s e t h e a n i m a l t o t i s s u e damage from ADR. C o n s i s t e n t w i t h t h i s c o n c e p t , Meyers e t a l . (34) have r e p o r t e d t h a t p r e t r e a t m e n t w i t h s u p p l e m e n t a l v i t a m i n E c a n reduce t h e t o x i c i t y o f ADR i n mice.



NUTRITIONAL

BIOAVAILABILITY

O F MANGANESE

F i g u r e 3. H e a r t m i t o c h o n d r i a from a c o n t r o l mouse showing normal u l t r a s t r u c t u r e (x 22,000).

F i g u r e 4. H e a r t m i t o c h o n d r i a from an ADR-treated d i e t low i n v i t a m i n E and Mn (x 22,000).

mouse f e d a


6. ZIDENBERG-CHERR AND KEEN

Enhanced Tissue Lipid Peroxidation 65

Summary In the above it is evident that a consequence of Mn deficiency can be a profound reduction in MnSOD activity. Data from lipid peroxidation studies strongly support the concept that this reduction is of functional significance. In addition, the above findings demonstrate the fact that environmental insults and drugs which exert their toxic effects through the production of 0^ may exacerbate the effects of Mn deficiency. However, it is evident from the work on ozone and ADR that the response of Mn-deficient animals to free radical generators can vary. This suggests that the response to such insults may be tissue specific and/or dependent on the total amount of free radical generated. Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: October 5, 1987 | doi: 10.1021/bk-1987-0354.ch006

Literature Cited 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Orent, E. R.; McCollum, E. V. J . Biol. Chem. 1931, 92, 651-78. Kemmerer, A. R.; Elvehjem, C. A.; Hart, E. B. J. Biol. Chem. 1931, 92, 623-30. Keen, C. L . ; Lonnerdal, B. In Manganese in Metabolism and Enzyme Function; Schramm, V. L. and Wedler, F. C., Eds.; Academic: Orlando, FL, 1986; pp 35-49. Vallee, B. L . ; Coleman, J. E. In Comprehensive Biochemistry; Florkin, M. and Stotz, E . , Eds.; Elsevier: New York, 1964; Vol. 12, pp 165-235. Leach, R. M., Jr. In Manganese in Metabolism and Enzyme Function; Schramm, V. L. and Wedler, F. C., Eds.; Academic: Orlando, FL, 1986; pp 81-92. Antonini, E.; Brunori, M.; Greenwood, C.; Malmstrom, B. G. Nature 1970, 228, 936-7. Clark, I. A. Pathology 1986, 18, 181-6. Halliwell, B. Medical Biology 1984, 62, 71-7. Beyer, W. F . , Jr.; Fridovich, I. In Manganese in Metabolism and Enzyme Function; Schramm, V. L. and Wedler, F. C., Eds.; Academic: Orlando, FL, 1986; pp 193-217. Tappel, A. L. In Free Radicals in Biology; Pryor, W., Ed.; Academic: New York, 1980; Vol. IV, pp 1-47. deRosa, G.; Keen, C. L . ; Leach, R. M.; Hurley, L. S. J . Nutr. 1980, 110, 795-804. Paynter, D. L. J . Nutr. 1980, 110, 437-47. Greengard, O. Assays Biochem. 1971, 7, 159-203. Yoshioka, T.; Utsunio, K.; Sekiba, K. Biol. Neonate 1977, 32, 147-53. Lankin, V. Z.; Tikhaze, A. K.; Lemeshko, V. V.; Shermatov, K.; Kaliman, L. A.; Vikhert, A. M. Byulletin Eksperimental noi Biologii i Meditsiny 1981, 92, 310-11. Mavelli, I.; Rigo, A.; Federico, R.; Ciriolo, M.; Rotilio, G. Biochem. J . 1982, 204, 535-40. Zidenberg-Cherr, S.; Keen, C. L . ; Casey, S. M.; Hurley, L. S. Biol. Trace Element Res. 1985, 7, 209-19. Zidenberg-Cherr, S.; Keen, C. L . ; Lonnerdal, B.; Hurley, L. S. J. Nutr. 1983, 113, 2498-504.


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19. 20. 21. 22. 23. 24. 25. Downloaded by UNIV LAVAL on July 11, 2016 | http://pubs.acs.org Publication Date: October 5, 1987 | doi: 10.1021/bk-1987-0354.ch006

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