Chelate Therapy for Type b Metal Ion Poisoning - American Chemical

The fact that type b/soft metal ions (for our purposes those that form stronger ..... as nitrogen/sulfur seekers by Nieboer and Richardson (42) on the...
0 downloads 0 Views 1MB Size
Download PDF
19 Inorganic Chemistry in Biology and Medicine Downloaded from pubs.acs.org by UNIV OF CALIFORNIA SANTA BARBARA on 09/19/18. For personal use only.

Chelate Therapy for Type b Metal Ion Poisoning MARK M . JONES and MARK A. BASINGER Department of Chemistry and Center in Environmental Toxicology, Vanderbilt University, Nashville, T N 37235

The fact that type b/soft metal ions (for our purposes those that form stronger coordinate bonds to S than to O) have their own distinctive set of coordination preferences has clear consequences for both the distribution of these metals in the mammalian body and the most effective reagents for use in facilitating their re­ moval. Their toxicity is presumably due to the combined action of their coordination preferences and their stereochemistry in the determination of those biological binding sites which are prefer­ entially attacked and subsequently inactivated. For purposes of the present discussion we will use a combination of the classifi­ cation schemes of Ahrland, Chatt and Davies (1) and Pearson (2). Of the elements which fall in this broad category, many are so un­ commonly encountered clinically that human cases are extraordinar­ ily rare. The elements for which some information is available on body distribution and decorporation will be the ones on which our attention will be centered. These include Hg(II), Au(II), As(III), Sb(III), Cu(I), and Pt(II). It is necessary to note that there are differences in the or­ gan distribution of these elements and that the processes involved in their metabolism are generally complex and imperfectly under­ stood. However, type b metals do, by and large, show a tendency to accumulate in the kidneys and liver; renal failure (nephrotic syndrome) seems to be a common result of their action. When the "natural" half-life of these elements in the mammalian body is ex­ amined, it is generally found that the rate processes correspond to the loss of the element from two or more compartments (3,4) in which the stability of the metal to biological molecule bonds vary greatly. As a result, it is somewhat misleading to quote a single half-life as characteristic of the loss of the metal from the whole animal. Furthermore, the relative amount of a metal which goes into these different compartments can vary with both the rate of loading and the time interval between the metal loading and the analysis. This brings into somewhat clearer focus the problem of metalbinding sites in whole animals. The sites with the shortest 0-8412-05 8 8-4/ 80/47-140-3 35 $05.00/0 © 1980 American Chemical Society

336

INORGANIC

CHEMISTRY

IN

BIOLOGY

AND

MEDICINE

h a l f - l i v e s seem to be those i n which the h a r d / s o f t p r o p e r t i e s o f the metal and donor s p e c i e s are r a t h e r p o o r l y matched. Thus s i t e s i n which Hg(II) i s bonded to 0 would be expected to r e l e a s e the Hg(II) more r e a d i l y than those i n which i t i s bonded to S. As time goes by, that part o f the metal which remains i n the body can bind to s i t e s with which i t forms s u c c e s s i v e l y more s t a b l e complexes. As t h i s occurs, the removal o f the metal from the body may become i n c r e a s i n g l y more d i f f i c u l t . This p a r t i c u l a r problem i s of great importance i n d e a l i n g with chronic metal p o i s o n i n g , e s p e c i a l l y among i n d u s t r i a l workers exposed to lead and cadmium (4) . Very o f t e n these cases become apparent o n l y a f t e r extended exposure, d u r i n g which time a large p a r t of the t o t a l body burden has been t r a n s f e r r e d to s i t e s from which i t s removal i s extremely d i f f i c u l t or impossible. In lead p o i s o n i n g the accumulation i s i n the bones; i n cadmium p o i s o n i n g the accumulation i s i n the kidneys and perhaps the t e s t e s . In many types of metal p o i s o n i n g , there appears to be an approximately maximum a l l o w a b l e time i n t e r v a l between i n t o x i c a t i o n and the i n i t i a t i o n of c h e l a t e therapy. When treatment i s begun a f t e r t h i s i n t e r v a l , the extent and i r r e v e r s i b i l i t y o f the damage i s such that the death o f the organism can be assumed t o f o l l o w no matter how much a n t i d o t e i s administered; f o r l e s s than t o x i c doses an analogous phenomenon i s the occurrence o f permanent damage. The chemical b a s i s o f t h i s time p e r i o d may not be uniform f o r a l l of the type b metals. For mercury(II) i t appears to be r e l a ted to the occurrence of a minimum amount of what i s l i t e r a l l y the d e s t r u c t i o n of t i s s u e and p r o t e i n s . In the case o f cadmium i t appears to have a d i f f e r e n t b a s i s at l e a s t i n p a r t . Subsequent to the i n j e c t i o n of an otherwise l e t h a l dose of a cadmium compound there i s a r e l a t i v e l y short p e r i o d when i t can be complexed and removed and the animal saved. As the i n t e r v a l between the cadmium i n j e c t i o n and that of the a n t i d o t e (e.g. CaEDTA or CaDTPA) i n creases, the cadmium becomes more and more d i f f i c u l t to m o b i l i z e and a p o i n t i s soon reached where the a n t i d o t e i s without e f f e c t (5) . In the same f a s h i o n , aged cadmium d e p o s i t s are apparently r e s i s t a n t to m o b i l i z a t i o n by EDTA (6). General Procedures With t h i s as a background, we may now examine the procedures a v a i l a b l e f o r the removal o f such metals. The normal r o u t e cons i s t s i n the r e a c t i o n o f the deposited metal with a c h e l a t i n g agent with which i t forms a water s o l u b l e complex. This metal complex i s then excreted through the kidneys i n t o the u r i n e . Because the kidneys are themselves a d e l i c a t e and complex organ t h i s process i s attended by a c e r t a i n inherent danger. I t i s i n the matching up of these metal ions with the most a p p r o p r i a t e c h e l a t i n g agents that c o o r d i n a t i o n chemists can make a s i g n i f i c a n t contribution. Let us f i r s t look at some o f the requirements which

19.

J O N E S A N D BASINGER

Metal

Ion

Poisoning

337

these c h e l a t i n g agents must meet. Desiderata f o r i d e a l therapeut i c c h e l a t i n g agents i n c l u d e the f o l l o w i n g : 1. They must possess an i p LD50 > 400 mg/kg. 2. They must form very s t a b l e complexes with the metal i o n whose removal i s d e s i r e d . 3. Any s e l e c t i v i t y which they e x h i b i t i n forming complexes i s u s u a l l y advantageous i f other adverse p r o p e r t i e s are not simultaneously enhanced. 4. The complexes formed should be water s o l u b l e . 5. The passage o f the complexes through the kidneys should be accompanied by a minimum o f damage. 6. I t i s probably h e l p f u l i f the c h e l a t i n g agents undergo no s i g n i f i c a n t metabolism. It i s necessary to note that these complexes may be mixed complexes i n v o l v i n g the c h e l a t i n g agent the metal and some b i o l o g i c a l molecule and the mixed complex i s then the metal c o n t a i n i n g species which passes through the kidneys (7). The t o x i c i t y o f c h e l a t i n g agents i s an area i n which the gene r a l f e a t u r e s are becoming known i n great d e t a i l as more data i s c o l l e c t e d . To begin, the d a i l y a d m i n i s t r a t i o n o f a p p r e c i a b l e amounts o f almost any good c h e l a t i n g agent i s u l t i m a t e l y t o x i c or l e t h a l because o f the enhanced u r i n a r y e x c r e t i o n o f e s s e n t i a l t r a c e elements which i t provokes. Some c h e l a t i n g agents, such as the aminopolycarboxylates, which undergo l i t t l e i f any metabolic changes i n the human body, appear to act as t o x i c m a t e r i a l s almost e x c l u s i v e l y v i a t h e i r a b i l i t y to upset metal i o n e q u i l i b r i a o f various s o r t s i n the human or animal body. When administered as calcium or z i n c complexes, they have a very modest t o x i c i t y i n deed, much reduced from that o f the parent compound. For c h e l a t i n g agents which can be metabolized, the t o x i c i t y a r i s e s from the d e p l e t i o n o f e s s e n t i a l t r a c e metals p l u s the metabolic a c t i v i t y o f the c h e l a t i n g agent. S u l f h y d r y l groups can i n t e r a c t with b i o l o g i cal redox systems and derange them. For such compounds a high l i p i d s o l u b i l i t y i s o f t e n a s s o c i a t e d with a high t o x i c i t y . T h i s high l i p i d s o l u b i l i t y a l s o allows the metal complexes which are formed to i n t r u d e i n t o areas normally p r o t e c t e d by l i p i d b a r r i e r s , such as the b r a i n (8). I t i s f o r t h i s reason that the "best" o f such c h e l a t i n g agents f o r our purposes are those which possess a very high water s o l u b i l i t y (and a correspondingly low l i p i d s o l u b i l i t y ) f o r both the parent compound and the metal complexes which are formed i n the d e t o x i f i c a t i o n process. The s t r u c t u r e s o f some of the t h e r a p e u t i c c h e l a t i n g agents which are used f o r the type b/ s o f t ions are shown i n Table I. These have one or more s u l f u r donor groups plus other groups to enhance the water s o l u b i l i t y o f both the compound and i t s metal complexes. T h i s enhancement i s to be understood i n the r e l a t i v e sense that the water s o l u b i l i t y i s greater than i n the corresponding d e r i v a t i v e s without such groups. The absolute s o l u b i l i t y of the metal complexes formed may s t i l l be q u i t e s m a l l . The t o x i c i t i e s o f these, o f some other

INORGANIC

338

CHEMISTRY

IN

BIOLOGY

AND

MEDICINE

t h e r a p e u t i c a l l y u s e f u l c h e l a t i n g agents and some c h e l a t i n g agents which are not so used are l i s t e d i n Table I I . A c h e l a t i n g agent w i l l not always use a l l o f i t s donor groups when i n t e r a c t i n g with LD50 Values o f Therapeutic and Non-therapeutic C h e l a t i n g Agents C h e l a t i n g Agent

LD50 mg/kg

Na CaEDTA Na^EDTA D-penici1lamine N-Acetyl-D,L-penicillamine Ethylenediamine 2,3-dimercaptopropanesulfonate Triethylenetetramine BAL S a l i c y c l i c Acid Acetylacetone Deferrioxamine 2,3-dimercaptosuccinate sodium Dimethylglyoxime 2

3800 380 334 1000 427 2000 4340 105 891 1000 329 5000 250

Conditions rat, i.p. mouse, i . p . mice, i . p . rats, i.p. mouse, s.c. mouse, s.c. rat, oral rat, i.v. rat, oral rat, oral rat, i.v. mouse, o r a l rat, oral

Lit. a a b b a c a a a a d e a

M

a. "Toxic Substances 74 U.S. Dept. HEW, R o c k v i l l e , Md. b. Aposhian, H. V.; Aposhian, M. M. Pharmacol. E x p t l . Ther., 1959, 126, 131. c. Klimova, L. K. Farmakol. i T o k s i l s o l . , 1958, 21, 53. d. Goldenthal, Ε. I. Tox. Appld. Pharmac., 1971, _18, 185. e. S t o h l e r , H. R.; Frey, J . R. Ann. Trop. Med. P a r a s i t o l . , 1964, 58(4),

431.

One o f the strange problems of metal i o n t o x i c i t y i s the lack o f a d i r e c t r e l a t i o n s h i p between the s t a b i l i t y constant o f a metal-chelate complex and the a b i l i t y o f that c h e l a t i n g agent to o f f s e t the acute t o x i c i t y o f that metal i o n . There i s a good t h e o r e t i c a l model o f the r e l a t i o n s h i p between metal c h e l a t e s t a ­ b i l i t y constants and the decorporation process (9,10,11) f o r groups o f c l o s e l y r e l a t e d c h e l a t i n g agents. Part o f t h i s problem l i e s i n the f a c t that the s t a b i l i t y constants f o r many metalc h e l a t e combinations of i n t e r e s t simply have not been determined with the r e q u i r e d degree o f accuracy. Nevertheless, i t i s gener­ a l l y accepted that i f a c h e l a t i n g agent i s to be a s u c c e s s f u l a n t i d o t e f o r a given t o x i c metal i t must form complexes with that metal which are more s t a b l e than the complexes which that metal forms with the b i o l o g i c a l b i n d i n g s i t e s . Given t h i s then, how does one guarantee that the c h e l a t i n g agent can gain access to the bound metal perhaps w i t h i n the c e l l ? T h i s i s a d i f f i c u l t question to answer but i t does o f t e n seem that the c e l l w a l l s are i n f a c t f a r more permeable to water s o l u b l e c h e l a t i n g agents than has p r e v i o u s l y been supposed. The f a c t i s that these compounds can remove metals which are bound to s t r u c t u r e s i n s i d e the c e l l s .

19.

J O N E S A N D BASINGER

Metal

Ion

Poisoning

339

There are r e a l l y two e a s i l y envisaged mechanisms by which t h i s might occur. In the f i r s t , (Figure 1) the c h e l a t i n g agent passes through the membrane, i n one manner or another, comes i n d i r e c t contact with the metal i o n , p u l l s i t o f f the b i o l o g i c a l b i n d i n g s i t e , t r a n s p o r t s i t back through the c e l l u l a r membrane to the i n ­ t r a c e l l u l a r f l u i d and then c a r r i e s i t through the kidneys and i n t o the u r i n e . In the second mechanism (Figure 2) the c h e l a t i n g agent need not a c t u a l l y penetrate the c e l l w a l l i f a system i n v o l v i n g appropriate c a r r i e r molecules i s present. C e l l u l a r membranes are now recognized as being more permeable to c e r t a i n types o f small molecules and the f i r s t mechanism i s no longer considered so improbable. In e i t h e r mechanism the more e f f e c t i v e matching up o f the donor/acceptor p r o p e r t i e s can be seen to lead to an i n c r e a s e d efficacy. D e t o x i f i c a t i o n and Decorporation o f S p e c i f i c Metal

Ions

The metal ions considered here are those which bond p r e f e r e n ­ t i a l l y to S donors, e s p e c i a l l y s u l f h y d r y l groups. The bonds to 0 or Ν can g e n e r a l l y be broken by an appropriate s u l f h y d r y l group, though the p e c u l i a r c o o r d i n a t i o n chemistry i n these s i t u a t i o n s does not always lead to e i t h e r c h e l a t e r i n g s c o n t a i n i n g two s u l f u r donors or a complete replacement o f 0 or Ν donors by S (12,13). These ions are not always d e r i v e d from type b elements i n the usual c l a s s i f i c a t i o n scheme. Thus As i s put i n c l a s s a on the ba­ s i s o f the behavior of As(V). But the reducing powers o f c e l l u l a r media may (43) transform As(V) to A s ( I I I ) , whose c o o r d i n a t i o n be­ h a v i o r shows a marked preference f o r S donors over those o f 0 or N. The same i s t r u e o f Sb. For copper an analogous process can be used to transform the b o r d e r l i n e species Cu(II) to one i n which preferences f o r bonding to S are more marked, i . e . Cu(I) i n order to f a c i l i t a t e i t s e x c r e t i o n . Mercury. Mercury(II) and the v a r i o u s organic d e r i v a t i v e s o f mercury do not have the same p a t t e r n o f e i t h e r body d i s t r i b u t i o n or response to c h e l a t i n g agents (14). The h a l f - l i f e o f mercury (II) i n the human body i s r e l a t i v e l y short (3). The c r i t i c a l pe­ r i o d i n mercury poisoning i s apparently the p e r i o d immediately f o l l o w i n g the i n t r o d u c t i o n o f the compound i n t o the body. During t h i s p e r i o d the extent of damage i n c r e a s e s with time and the por­ t i o n o f t h i s which represents permanent, apparently i r r e p a i r a b l e damage a l s o increases with time. A f t e r t h i s has reached a c e r t a i n p o i n t there i s a l i m i t to the extent o f the h e a l i n g that w i l l oc­ cur. In humans t h i s has the consequence that a f t e r c e r t a i n stages of poisoning the a c c e l e r a t e d removal o f the mercury from the human body has r e l a t i v e l y l i t t l e e f f e c t on the c l i n i c a l s t a t e o f the p a t i e n t (15). S u l f h y d r y l b e a r i n g compounds of v a r i o u s s o r t s are by f a r the best agents yet discovered f o r a c c e l e r a t i n g the removal o f

INORGANIC

340

Extracellular Fluid

TT

Cell Wall

CHEMISTRY IN

BIOLOGY

AND

MEDICINE

Intracellular Fluid

Cell Wall

T T Chelating Agent • Toxic Metal Ion Figure 1. Mechanism A: overall process by which a chelating agent can remove a toxic metal ion from a cell when the cell wall is permeable to the chelating agent

Extracellular Fluid

Cell Wall

Intracellular Fluid Ο

TT

TT

Cell Wall T T Chelating Agent • Toxic Metal ion Ο Carrier Biomolecule Figure 2. Mechanism B: overall process by which a chelating agent can remove a toxic metal ion from a cell when the cell wall is impermeable to the chelating agent

19.

Metal

J O N E S A N D BASINGER

341

Ion Poisoning

mercury(II) and organomercury compounds from the mammalian body. The r e s u l t s o f a comparative study o f the e f f i c a c y o f some o f these compounds i n o f f s e t t i n g the l e t h a l i t y due t o i p H g C l i s shown i n Table I I I (16). Of the compounds l i s t e d i n t h i s t a b l e , 2

Table III S u r v i v a l Rates f o r Various C h e l a t i n g Agents A l l animals given H g C l i . p . at a l e v e l o f 10 mg/kg 2

Mole Ratio Chelator/HgCl

Chelator

2

a

Survival Ratio

30 30 30 30 30

1 1 1 1 1

DMSA DMPS NAPA DPA BAL

14/20 16/20 15/20 17/20 1/20

10 10 10 10 10

1 1 1 1 1

DMSA DMPS NAPA DPA BAL

19/50 30/50 30/50 26/50 19/50

a. DMSA = 2,3-dimercaptosuccinic a c i d DMPS = sodium 2,3-dimercaptopropanesulfonate NAPA = N-Acetyl-D,L-penicillamine DPA = D - p e n i c i l l a m i n e BAL = 2,3-dimercaptopropanol-l (The s u r v i v a l r a t e o f untreated animals i s l e s s than 5%.) BAL may s t i l l be the most widely used i n human cases o f mercury poisoning, but the others would probably be found t o be more e f f e c t i v e under most c o n d i t i o n s , and t o produce fewer s i d e e f f e c t s . The compounds which are l i s t e d i n Table I I I other than BAL, a l l appear t o posses a r a t h e r low l i p i d s o l u b i l i t y and are r a p i d l y c l e a r e d from the human body through the kidenys. In an attempt t o extend the range o f donor species useable f o r mercury poisoning we have c a r r i e d out an e v a l u a t i o n o f the use of the phosphine (C6H ) PC6Hi S0 Na (17) . The phosphine was, i n f a c t , able t o o f f s e t some o f the p a t h o l o g i c a l changes c h a r a c t e r i s t i c o f mercuric c h l o r i d e p o i s o n i n g . I t s own inherent t o x i c i t y was too great, however, and the combined e f f e c t o f phosphine plus H g C l proved more l e t h a l than e i t h e r alone, Table IV. The p o s s i b i l i t y o f using a water s o l u b l e phosphine f o r mercury poisoning i s a remote one i n the absence o f compounds o f t h i s s o r t possessing a low inherent t o x i c i t y . Analogous data c o l l e c t e d on some water s o l u b l e dithiocarbamates which have more than one f u n c t i o n a l group (to assure water s o l u b i l i t y ) r e v e a l e d that these are both m a t e r i a l s o f modest i n herent t o x i c i t y and p o t e n t i a l use i n heavy metal poisoning (18). These dithiocarbamates do not possess e x c e p t i o n a l chemical 5

2

2

+

3

INORGANIC

342

CHEMISTRY

IN

BIOLOGY

AND

MEDICINE

Table IV S u r v i v a l Ratios f o r Mice Given Diphenylphosphinebenzenesulfonate As An A n t i d o t e f o r H g C l , i . p . 2

Compounds Administered HgCl DPPBS DPPBS H g C l + DPPBS H g C l + DPPBS 2

2

2

Survivors Total

Amounts Administered 8 mg HgCl 0.2 mmole 0.3 mmole 8 mg HgCl 8 mg HgCl

2

2

2

/kg DPPBS/kg DPPBS/kg /kg +0.2 mmole DPPBS/kg /kg +0.3 mmole DPPBS/kg

3/10 8/10 7/10 1/15 0/10

s t a b i l i t y , though they are e a s i e r to prepare than most o f the typi c a l c h e l a t i n g agents which c o n t a i n s u l f u r donors. They are not as e f f e c t i v e i n o f f s e t t i n g l e t h a l i t y i n acute mercuric c h l o r i d e poisoning as the s u l f h y d r y l compounds l i s t e d i n Table I I I . The most common o f the dithiocarbamates a v a i l a b l e as a pure l a b o r a t o r y chemical i s d i e t h y l dithiocarbamate, a compound which gives l i p i d s o l u b l e metal complexes. T h i s has been t r i e d i n a few types o f metal poisoning without notable success (19). T h i s compound seems i n h e r e n t l y l e s s promising f o r such a n t i d o t a l a c t i o n than analogous compounds which we have prepared which bear a d d i t i o n a l p o l a r groups. In s p i t e o f the f a c t that e f f e c t i v e c h e l a t i n g agents are a v a i l a b l e f o r the removal o f mercury from the mammalian body, the chemistry o f these i n t e r a c t i o n s , the s t r u c t u r e s o f the complexes formed and many aspects o f t h e i r mechanism o f a c t i o n are s t i l l unknown q u a n t i t i e s . One o f the key p r o p e r t i e s o f a donor-metal i n t e r a c t i o n i n judging the s u i t a b i l i t y o f the donor as a t h e r a p e u t i c agent f o r the metal i s the s t a b i l i t y constant o f the complex formed. We have r e c e n t l y completed a study which t r i e d t o i n t r o duce some system i n t o the i n f o r m a t i o n on these parameters f o r mercury complexes o f i n t e r e s t i n therapy. Using a three e l e c t r o d e system we determined estimates o f the s t a b i l i t y constants f o r many of these (Table V) (20). A s t r i k i n g f e a t u r e o f these are t h e i r Table V S t a b i l i t y Constants o f Mercury(II) Complexes With S u l f h y d r y l Containing Donors Donor Molecule D-penicillamine N-Acetyl-D,L-penicillamine 2,3-Dimercaptopropanesulfonate 2,3-Dimercaptopropanol-l 2,3-Dimercaptosuccinic A c i d Mercaptoacetic A c i d Mercaptoethanesulfonate N-Acetylcysteine

log Ki 38.,3 35.,4 42.,2 44.,8 39.,4 36..5 36 38.,1

log

K

2

6.1 6.2 10.9 7.11 6.5 5.9 6 7.5

19.

J O N E S A N D BASINGER

Metal

Ion

Poisoning

343

large magnitudes. While i t i s reasonably c e r t a i n that these com­ plexes are a l l more s t a b l e than the corresponding Hg-EDTA complex, i t i s p o s s i b l e that t h e i r s t a b i l i t y constants are overestimated here because o f some systematic e r r o r . The r e s u l t s are i n agree­ ment with some e a r l i e r s t u d i e s on t h i s same problem (21,22) i n v o l ­ v i n g mercury(II) complexes with c y s t e i n e and HS~. A r s e n i c . A r s e n i c poisoning i s g e n e r a l l y regarded as i n v o l ­ v i n g , i n a key step, the r e a c t i o n of arsenious a c i d or a d e r i v a ­ t i v e with s u l f h y d r y l groups i n c r i t i c a l enzymes (23), e.g. pyruvate oxidase. Because a r s e n i c ( I I I ) favors c o o r d i n a t i o n to s u l f u r over that to n i t r o g e n or oxygen, the s i t u a t i o n here has some s i m i l a r i t i e s to that found with mercury. An important d i f ­ ference here however i s the general acceptance o f the hypothesis that c h e l a t i o n o f the a r s e n i c ( I I I ) by two s u l f h y d r y l s u l f u r s i s i n v o l v e d i n the a c t i o n o f e f f e c t i v e c h e l a t i n g agents. The most e f f e c t i v e o f the c h e l a t i n g agents are those which c o n t a i n v i c i n a l s u l f h y d r y l groups: BAL, sodium 2,3-dimercaptopropanesulfonate, and 2,3-dimercaptosuccinic a c i d . These are capable o f competing with the enzymes f o r the a r s e n i c . They transform i t i n t o a water s o l u b l e form and f a c i l i t a t e i t s e x c r e t i o n through the kidneys. Because BAL i s so e f f e c t i v e i n a r s e n i c poisoning and because t h i s kind of poisoning i s not as common as formerly, r e l a t i v e l y l i t t l e e f f o r t has been expended i n the search f o r new a r s e n i c a n t i d o t e s over the past twenty years. On the b a s i s o f animal s t u d i e s i t ap­ pears that any o f the c h e l a t i n g agents which c o n t a i n v i c i n a l s u l f ­ h y d r y l groups and are e f f e c t i v e with other heavy metals are e f f e c t i v e with a r s e n i c ( I I I ) . Antimony. Antimony(III) i s the a c t i v e c o n s t i t u e n t o f a l a r g e number o f drugs designed to k i l l human and animal p a r a s i t e s (24, 25). As a consequence o f the s i g n i f i c a n t v a r i a t i o n i n human r e ­ sponse to these drugs, most antimony p o i s o n i n g appears to be i a t ­ rogenic i n o r i g i n . Because the c o o r d i n a t i o n preferences o f t r i v a l e n t antimony and a r s e n i c are so s i m i l a r , the same group o f v i c i n a l dimercaptides that are used with a r s e n i c p o i s o n i n g a l s o f u r n i s h the most e f f e c t i v e t h e r a p e u t i c agents f o r antimony poison­ ing, i . e . 2,3-dimercaptosuccinic a c i d (26), 2,3dimercaptopropanesulfonate (27), and 2,3-dimercaptopropanol-l (28). The p r i n c i p a l t h e r a p e u t i c use o f antimony complexes l i e s i n the treatment o f diseases t y p i c a l o f t r o p i c a l zones. As a r e s u l t i a t r o g e n i c antimony poisoning i s r a t h e r uncommon i n the United States or Europe. G o l d ( I ) . Gold(I) compounds are widely used i n the treatment of a r t h r i t i s (29). These compounds are g e n e r a l l y ones i n which the gold i s coordinated to a s u l f u r atom (e.g. as i n Na [Au(S 03) ] or i n complexes with organic mercaptides). Gold(I) c o o r d i n a t i o n preferences run as: 0 < Ν < S, with S donors apparently able to r e p l a c e 0 or Ν with ease. There are s i g n i f i c a n t i n d i v i d u a l 2

2

2

INORGANIC

344

CHEMISTRY

IN

BIOLOGY

AND

MEDICINE

v a r i a t i o n s i n the response o f p a t i e n t s to gold therapy inasmuch as the immune system i s i n v o l v e d . The occurrence o f s i d e e f f e c t s i n v o l v i n g the kidneys are not unknown and i t i s o c c a s i o n a l l y necessary to enhance the e x c r e t i o n of the gold which has been administered. C l i n i c a l l y , a l l of the compounds l i s t e d as used i n mercury poisoning have a l s o found use i n the treatment o f gold poisoning i n a r t h r i t i c p a t i e n t s . L i t t l e information seems to be a v a i l a b l e on the comparative e f f i c a c y of the various compounds which have been used f o r t h i s purpose. D-penicillamine and NA c e t y l - D , L - p e n i c i l l a m i n e appear to be p r e f e r r e d i n the United States and Western Europe because o f t h e i r low t o x i c i t y and the ease with which they can be obtained and given; both o f these compounds can be administered o r a l l y . The incidence o f s i d e react i o n s i n gold therapy i s f a i r l y high 020%) and a small percentage of these i s very s e r i o u s . Like other c l a s s b or s o f t metals, gold can accumulate i n and cause damage to the kidneys. Copper. Copper(II) i s one o f the b o r d e r l i n e species whose behavior f a l l s between that of type a and type b s p e c i e s . It i s e a s i l y reduced to copper(I) i n the presence of s u l f h y d r y l groups and t h i s r e a c t i o n i s a p a r t o f the o v e r a l l process when copper exc r e t i o n i s enhanced by s u l f h y d r y l c o n t a i n i n g c h e l a t i n g agents (30). I t s e x c r e t i o n can a l s o be a c c e l e r a t e d by species which are not capable o f reducing copper(II) to copper(I), such as t r i e t h y lenetetramine (31). As a r e s u l t of the fundamental long-term studies o f Walshe (32) on the treatment o f h e r e d i t a r y copperaccumulating d i s o r d e r s , very e f f e c t i v e treatments are now a v a i l able f o r the treatment o f chronic copper poisoning. The most e f f e c t i v e of these use D-penicillamine to enhance u r i n a r y excret i o n o f copper. This i n v o l v e s an i n i t i a l r e d u c t i o n to copper(I) followed by the u r i n a r y e x c r e t i o n o f the copper(I) complex. A complication may a r i s e i n i n d i v i d u a l s who are a l l e r g i c to p e n i c i l l i n - these a l s o have an a l l e r g i c response to D - p e n i c i l l a m i n e . It i s f o r these i n d i v i d u a l s that Walshe developed the use o f t r i e t h y lenetetramine as an a l t e r n a t i v e compound capable o f enhancing the u r i n a r y e x c r e t i o n o f copper. Platinum(II). The recent upsurge i n the use o f platinum meta l complexes i n cancer chemotherapy, has l e d to an increased app r e c i a t i o n o f t h e i r t o x i c i t y . The most widely used of these m a t e r i a l s , cis[Pt(NH3)2Cl2] i s a m a t e r i a l which i s q u i t e t o x i c , but a l s o comparatively i n s o l u b l e . As a consequence i t i s administ e r e d as a d i l u t e s o l u t i o n , o f t e n v i a i v d r i p . Since platinum(II) i s i n many ways a t y p i c a l c l a s s b i o n , i t can g e n e r a l l y be mobili z e d by the same group o f c h e l a t i n g agents which have been found to be e f f e c t i v e f o r mercury(II) or g o l d ( I ) . The n e p h r o t o x i c i t y which i s a common feature of the use o f t h i s compound (32,33,34) can o f t e n be reduced by appropriate h y d r a t i o n o f the p a t i e n t s (35). Reports o f the use o f c h e l a t i n g agents to o f f s e t the t o x i c e f f e c t s of c i s [ P t ( N H ) C l ] are not common but D - p e n i c i l l a m i n e has 3

2

2

19.

JONES

AND

BASINGER

Metal

Ion

Poisoning

345

been reported to reduce the n e p h r o t o x i c i t y o f t h i s compound (36). Unfortunately t h i s a l s o l i m i t s the a c t i o n o f the c i s complex against the cancer c e l l s . There i s no reason to b e l i e v e that the other complexing agents shown i n Table I would not be j u s t about as e f f e c t i v e as D - p e n i c i l l a m i n e i n l i m i t i n g the n e p h r o t o x i c i t y o f the c i s [ P t ( N H ) C l ] . 3

2

2

"Odd" O x i d a t i o n S t a t e s . The t o x i c i t i e s of the type b e l e ments are q u i t e markedly dependent upon t h e i r o x i d a t i o n s t a t e s and mode o f combination. These f a c t o r s a f f e c t both the mode of d i s t r i b u t i o n of these elements w i t h i n the mammalian body and the manner i n which they i n t e r a c t c h e m i c a l l y with enzymes and other c r i t i c a l biomolecules. In t h i s general area we f i n d problems posed by organomercurials, organoarsenicals and compounds such as a r s i n e and s t i b i n e . The t o x i c o l o g y o f these compounds tend to exh i b i t some s t r i k i n g d i f f e r e n c e s when compared with the compounds of these elements u s u a l l y encountered i n aqueous s o l u t i o n . To beg i n with, they o f t e n possess an e l e v a t e d s o l u b i l i t y i n l i p i d s and a correspondingly i n c r e a s e d a b i l i t y to pass through c e l l w a l l s and to pass over the s o - c a l l e d "blood b r a i n b a r r i e r " . As a consequence some of these substances are extremely t o x i c and are a l s o r a t h e r d i f f i c u l t to remove from the human body using water s o l u b l e c h e l a t i n g agents. A very c l e a r account o f these problems may be found i n the r e p o r t of Petrunkin and h i s co-workers d e s c r i b i n g t h e i r search f o r an e f f e c t i v e a n t i d o t e f o r a r s i n e p o i s o n i n g (37). They found that t y p i c a l water s o l u b l e c h e l a t i n g agents o f the s o r t which are very e f f e c t i v e i n the treatment o f poisoning by a r s e n i t e , were q u i t e i n e f f e c t i v e i n the treatment o f a r s i n e p o i s o n i n g . They a s c r i b e d t h i s to the poor l i p i d s o l u b i l i t y of these compounds which prevented them from g a i n i n g access to the c r i t i c a l s i t e s at which arsine acted. They solved t h i s problem by the design and s y n t h e s i s of appropriate l i p i d s o l u b l e compounds which contained v i c i n a l mercapto groups. Of these, the compound which they found most e f f e c t i v e i n animal studies on a r s i n e p o i s o n i n g was H H H HC—C—CH

Mixed Ligand Chelate Therapy. I t i s w e l l e s t a b l i s h e d that metal c h e l a t e complexes c o n s i s t i n g of two or more c h e l a t i n g agents possess an a d d i t i o n a l s t a b i l i t y over those c o n t a i n i n g j u s t a s i n g l e molecule o f one o f these c h e l a t i n g agents. T h i s has l e d to the p r e d i c t i o n that the a p p r o p r i a t e combination o f c h e l a t i n g agents should be more e f f e c t i v e than a s i n g l e one i n removing cert a i n metals from the mammalian body. The experimental i n f o r m a t i o n on the behavior o f mixed c h e l a t e systems i n acute cadmium

346

INORGANIC

CHEMISTRY

IN

BIOLOGY

AND

MEDICINE

poisoning i s c o n t r a d i c t o r y (38,39), but the e f f e c t may be present i n c e r t a i n s t u d i e s (40) i n v o l v i n g other elements. One of the d i f f i c u l t i e s attending such s t u d i e s i s the problem o f the a_ p r i o r i s e l e c t i o n o f the appropriate combination of chelat i n g agents. The question has been discussed b r i e f l y i n the l i t erature but there seems to be no e f f e c t i v e experimental t e s t i n g of the suggestions. In any d i s c u s s i o n by a chemist of the therapeutic usage of c h e l a t i n g agents i t i s p o s s i b l e to loose s i g h t of two important p o i n t s . The f i r s t i s that i t i s p o s s i b l e f o r a compound to serve as an antidote f o r say mercury poisoning even though i t does not have a p a r t i c u l a r l y notable a b i l i t y to enhance the e x c r e t i o n o f mercury (41). The second i s that a f t e r a s u f f i c i e n t l y long time i n t e r v a l between the i n t r o d u c t i o n of the metal, the r a p i d enhancement o f metal e x c r e t i o n from the human body does not n e c e s s a r i l y lead to any s i g n i f i c a n t c l i n i c a l improvement (15). Summary The most s t r i k i n g feature of a survey of t h i s s o r t i s to see that the optimum chelate therapy f o r the metals i n c l a s s b i s i n v a r i a b l y based upon the use of one of a small group of mercaptide bearing c h e l a t i n g agents (shown i n Table I ) . Furthermore, on the b a s i s of the work done i n t h i s area so f a r , i t seems reasonable to p r e d i c t that these same compounds would be e f f e c t i v e i n the t r e a t ment o f types of c l a s s b t o x i c i t y which have not yet been studied experimentally. Thus t o x i c i t y due to compounds of P d ( I I ) , Ag(I), R h ( I I I ) , and I r ( I I I ) should be o f f s e t by the t i m e l y a d m i n i s t r a t i o n o f these compounds. At the present time there i s no evidence to suggest that a s i n g l e one of these compounds w i l l be found to be the optimum agent f o r a l l of these ions or even that the sequence of e f f e c t i v e n e s s w i l l be the same when these compounds are t e s t e d against the d i f f e r e n t metal ions i n t h i s c l a s s . There i s however l i t t l e reason to doubt that the compounds shown i n Table I w i l l be at l e a s t p a r t l y e f f e c t i v e i n o f f s e t t i n g the t o x i c i t y of any of these i o n s . These, i n c i d e n t a l l y , are among those ions c l a s s i f i e d as n i t r o g e n / s u l f u r seekers by Nieboer and Richardson (42) on the b a s i s of X-ray s t r u c t u r a l information. Acknowledgement This work was c a r r i e d out under the auspices of the Center of Environmental Toxicology, Department of Biochemistry, V a n d e r b i l t U n i v e r s i t y School of Medicine, N a s h v i l l e , Tennessee, 37235 and supported by Grant 2R01ES01018-4 of the National I n s t i t u t e s of Environmental Health Sciences. I a l s o wish to thank N e i l H. Weinstein of the U n i v e r s i t y of F l o r i d a f o r h i s s t i m u l a t i n g and c r i t i c a l comments.

19.

JONES

Literature 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

13.

14. 15.

16. 17. 18.

19. 20. 21. 22. 23. 24. 25.

A N D BASINGER

Metal

Ion Poisoning

347

Cited

Ahrland, S.; Chatt, J.; Davies, N. R. Quart. Rev., 1958, 12, 265. Pearson, R. G., Ed. "Hard and Soft Acids and Bases"; Dowden, Hutchison & Ross:Stroudsburh, PA, 1973. Friberg, L.; Vostal, J., "Mercury in the Environment", CRC Press:Cleveland, OH, 1972; pp. 70-88. Tsuchiya, Κ., "Cadmium Studies in Japan: A Review", Kodansha Ltd.:Tokyo, 1978; pp. 76-79. Voight, G. E.; Skold, G. Z. Ges. Exper. Med., 1963, 136, 326. Friberg, L. A.M.A. Arch. Ind. Health, 1956, 13, 18. Walshe, J. M. Clin. Sci., 1964, 26, 461. Berlin, M.; Lewander, T. Acta Pharmacol., 1964, 22, 1. Schubert, J. Atompraxis, 1958, 4, 393 and the references cited therein. Catsch, Α., "Dekorpierung radioaktiver und stabiler Metallionen", Karl Thiemig:Munich, 1968; pp. 7-14. Heller, H.-J.; Catsch, A. Strahlentherapie, 1959, 109, 464. Canty, A. J. in "Organometals and Organometalloids", Brinckman, F. E.; Bellama, J. M., Eds., ACS Symposium Series 82, American Chem. Soc. Washington, D. C., 1978; pp. 327-338. Carty, A. J. in "Organometals and Organometalloids", Brinckman, F. E.; Bellama, J. M., Eds., ACS Symposium Series 82, American Chem. Soc. Washington, D. C., 1978; pp. 339-358. Swensson, Α.; Ulfvarson, J. Int. Arch. fur Gewerbepath. u. Gewerbehygiene, 1967, 24, 12. Bakir, F.; Al-Khalidi, Α.; Clarkson, T. W.; Greenwood, R. Bull. W.H.O., 1976, 53, 87, Suppl. "Conf. on Intoxication Due to Alkylmercury Treated Seed". Jones, M. M.; Basinger, Μ. Α.; Weaver, A. D.; Davis, C. M.; Vaughn, W. K. Res. Comm. Chem. Path. and Pharm. In press. Mitchell. W. M.; Holy, N. L.; Jones, M. M.; Basinger, Μ. Α.; Vaughn, W. K. Tox. Appl. Pharm. In press. Jones, M. M.; Burka, L. T.; Hunter, M. E.; Basinger, Μ. Α.; Campo, G.; Weaver, A. D. J. Inorg. Nucl. Chem., 1979, in press. Sunderman, F. W. Jr.; White, J. C.; Sunderman, F. W.; Lucyszym, G. W. Amer. J. Med., 1963, 34, 875. Casas, J. S.; Jones, M. M. J. Inorg. Nucl. Chem., 1979, in press. Stricks, W. Α.; Kolthoff, I. M. J. Am. Chem. Soc., 1953, 75, 5673. Schwarzenback, G.; Widmer, M. Helv. Chim. Acta, 1963, 46, 2613. Peters, R. A. "Biochemical Lesions and Lethal Synthesis", The Macmillan Co.:New York, 1963; pp. 40-58. Katz, M. Advances in Pharmacol. Chemother., 1977, 14, 1. Jordan, P.; Randall, K. Trans. Roy. Soc. Trop. Med. Hyg., 1962, 56, 136.

348 26. 27. 28.

29. 30. 31. 32. 33. 34. 35. 36. 37.

38. 39. 40. 41. 42. 43.

INORGANIC CHEMISTRY IN BIOLOGY AND MEDICINE

Chi, C.-T. Farmakol. i Toksikol., 1959, 22(1), 94. Chem. Abstr., 1959, 53, 20578. Stevenson, D. S.; Suarez, R. M. Jr.; Marchard, E. J. Puerto Rico J. Pub. Health Trop. Med., 1948, 23, 533. Walz, D. T.; Dimartino, M. J.; Suttin, Β. M. in "Antiinflam­ matory Agents", Scherrer, R.; Whitehouse, M. M., Eds., Aca­ demic Press:New York, 1974; Vol. 1, pp. 209-239. McCall, J. T.; Goldstein, N. P.; Randall, R. V.; Gross, J. B. Amer. J. Med., 1967, 254, 35/13. Walshe, J. Quart. J. Med. N. S., 1973, XLII, 441. Walshe, J. Brain, 1967, 90, 149. Madias, Ν. E.; Harrington, J. T. Amer. J. Med., 1978, 65, 307. Dentino, M.; Luft, F.; Yun, M. N.; Williams, S. D.; Einhorn, L. H. Cancer, 1978, 41, 1271. Gozalez-Vitale, J. C.; Hayes, D. M.; Cvitkovic, E.; Stern­ berg, S. S. Cancer Treat. Rep., 1978, 62, 693. Stark, J. J.; Howell, S. B. Clin. Pharmacol. Therap., 1978, 23, 461. Osieka, R.; Bruntsch, U.; Gallmeier, W. M.; Seeber, S.; Schmidt, C. G. Peutsch. Med. Wochschr., 1976, 101, 192. Mizyukova, I. G.; Petrunkin, V. E.; Lysenko, Ν. M. Farmakol. Tosikol (Moscow), 1971, 34(1), 70. Chem. Abstr., 1971, 74, 97223. Schubert, J; Derr, S. K. Nature, 1978, 275, 311. Jones, M. M.; Basinger, M. A. Res. Commun. Chem. Path. Pharmacol., 1979, 24, 525. Volf, V.; Seidel, Α.; Takada, L. Health Physics, 1977, 32, 155. Gabhard, B. Arch. Toxicol., 1976, 35, 15. Neiboer, E.; Richardson, D. H. S. Environmental Pollution (Series Β), 1979. In press. Ginsberg, J. M. Am. J. Physiol., 1965, 208, 832.

RECEIVED April 7, 1980.