Aspects of Mercury(II) Thiolate Chemistry and the Biological Behavior

20 Aspects of M e r c u r y ( I I ) T h i o l a t e C h e m i s t r y a n d the

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Biological B e h a v i o r of M e r c u r y C o m p o u n d s ALLAN J. CANTY Chemistry Department, University of Tasmania, Hobart, Tasmania, Australia

Complex formation between mercury compounds and thiols, e.g. cysteine, is believed to play a major role in the biological chemistry of mercury(1). The greater affinity of Hg(II) and MeHg(II) for thiols than other possible biological donor ligands has been well documented by stability constant studies in aqueous solution (2,3). Our interest in mercury(II) thiolates stems from studies of the chemistry of the antidote British anti-Lewisite which indicated that the structure and reactivity of simple thiolate complexes was little understood. In this review our recent work on the interaction of inorganic and organomercury compounds with British anti-Lewisite, simple thiols and sulphur containing amino acids is discussed, followed by an account of animal studies of the distribution and metabolism of phenylmercury compounds. In discussing the implications of chemical results, e.g. reactivity of thiolates, for the biological behaviour of mercury compounds it is assumed here that chemical studies provide only plausible pathways for biological behaviour. In recent years other workers have reported studies of mercury thiolates that are related to the work described here, in particular nuclear magnetic resonance studies of the interaction of MeHg(II) with thiols (4-9) and the preparation (10-16) and X-ray structural analysis of key complexes of Hg(II), MeHg(II), and PhHg(II) with sulphur containing amino acids (10-15). Complexes of British anti-Lewisite and other Thiols British anti-Lewisite [dimercaprol, 2,3-dimercaptopropanol; abbreviated BALH3 to indicate loss of thiol protons on complex formation, e.g. Hg(BALH)] has been used for the treatment of mercury poisoning in humans (17,18) and has been studied extensively in animal experimentsTl8-24). Although it may be eventually replaced by a more satisfactory treatment, e.g. hemodialysis (25,26), it is successful for poisoning by 0-8412-0461-6/78/47-082-327$05.00/0 © 1978 American Chemical Society In Organometals and Organometalloids; Brinckman, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.


328

ORGANOMETALS

AND

ORGANOMETALLOIDS

inorganic mercury (17,18) and i s the most s a t i s f a c t o r y a n t i d o t e f o r phenylmercury(II) poisoning [animal experiments only to date ( 1 8 ) ] , but has no therapeutic e f f e c t f o r methylmercury(II) poisoning i n humans or animals (18). For PhHg(II) poisoning BALH3 g r e a t l y increases the amount o f mercury i n the brain compared with the b o d i l y d i s t r i b u t i o n i n the absence of BALH3 treatment Q8,19.,20,2]_), and f o r MeHg(II) i t merely hastens the d i s t r i b u t i o n o f mercury and may increase the amount of mercury i n the b r a i n (18). An increased mercury content i n the b r a i n i s u n d e s i r a b l e , as i t attacks the c e n t r a l nervous system. BALH3 a l s o increases the amount o f mercury i n the b r a i n following i t s a d m i n i s t r a t i o n f o r inorganic mercury poisoning (22,23,24), but t h i s e f f e c t has been explained i n terms o f the timing and dosage of BALH3 (24). I s o l a t i o n o f Hg(BALH) (27,28) and evidence f o r the formation o f [ H g ( B A L H ) ] " (27), (PhHg) BALH (28), and (RHg) BALH „ [n = 1 (29), 2 T28); R = CH CH(0MiTCH R'] were reported by several workers soon a f t e r the I n t r o d u c t i o n o f BALH3 as an antidote f o r heavy metal p o i s o n i n g . Mercuric c h l o r i d e reacts immediately with BALH3 i n water to form a white s o l i d i d e n t i f i e d as Hg(BALH) (27,28,30*11)· 2

n

HgCl

3

2

2

n

2

2

+ BALH + Hg(BALH) + 2HC1

2

3

C r y s t a l s t r u c t u r e s of simple t h i o l a t e s Hg(SR)2 reveal e i t h e r l i n e a r monomers [R=Me (32), Et (33)] (Figure 1) or a polymeric s t r u c t u r e with t e t r a h e d r a l mercury (R=Bu ) (34) (Figure 2). Infrared and Raman spectra i n d i c a t e t h a t h i g h l y i n s o l u b l e Hg(BALH) has a polymeric s t r u c t u r e based on l i n e a r c o o r d i n a t i o n for mercury (31) (Figure 3 ) , r a t h e r than the c y c l i c s t r u c t u r e u s u a l l y presented (Figure 4 ) . Thus, Hg(BALH) has v c ( S H g S ) 348 and v (SHgS) 298 crrr», s i m i l a r to that o f Hg(SMe)2 (377 and 297 cm-1) and well removed from tetrahedral mercury i n Hg(SBut) (172 and 188 cm-1) (31). Spectroscopic p r o p e r t i e s appropriate f o r i d e n t i f i c a t i o n o f Hg(II) t h i o l a t e s , e . g . i n f r a r e d , Raman, and nuclear magnetic resonance, a r e presented elsewhere ( H , 3 5 , 3 6 , 3 7 , 3 8 , 3 9 ) . The simple t h i o l a t e s HgXSR7 are i n s o l u b l e i n water but s o l u b l e i n organic s o l v e n t s , e . g . Hg(SR) (R=Et,Bu ,Ph) are monomeric i n chloroform. Hg(BALH) i s i n s o l u b l e i n water, even a t concentrations o f c a . 10'^M (40). An impure form of Hg(BALH) can be i s o l a t e d by r e a c t i o n of mercuric acetate with BALH3 i n p y r i d i n e (35). T h i s s o l i d i s s o l u b l e i n p y r i d i n e , and the r e l a t e d complex o f 1,3-dimercaptopropanol, Hg(DMPH), can be i s o l a t e d from water and forms a dimer i n p y r i d i n e (35). The s t r u c t u r e o f Hg(DMPH) i n p y r i d i n e i s unknown but presumably involves p y r i d i n e c o o r d i n a t i o n , [Hg(DMPH)py ] , as i t c r y s t a l l i z e s as Hg(DMPH)py].5 c o n t a i n i n g coordinated p y r i d i n e . The s o l u b i l i t y o f impure Hg(BALH) i n p y r i d i n e i s o f i n t e r e s t as Hg(BALH) i s presumably formed i n many "environments" i n v i v o , t

a

s

2

2

t

2

x

2

In Organometals and Organometalloids; Brinckman, F., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

CANTY

Mercury Compounds


RS

Hg

SR

Figure 1.

Bu' S S V

Hg"

" Hg 1

Bu Figure 2.

Hg Figure 3.

Figure 4.


330

ORGANOMETALS

AND ORGANOMETALLOIDS

and p y r i d i n e s o l u b i l i t y suggests higher s o l u b i l i t y i n l i p i d t i s s u e than more aqueous r e g i o n s . The neutral complex may be present as a dimer [Hg(BALH)Lv] r e l a t e d to Hg(DMPH) i n p y r i d i n e , or p o s s i b l y as the c y c l i c complex (Figure 4) with a d d i t i o n a l ligands coordinated to mercury. In a l k a l i n e s o l u t i o n Hg(BALH) d i s s o l v e s on a d d i t i o n o f excess BALH3 suggesting (27) formation o f [Hg(BALH)2] ", and a d d i t i o n o f BALH3 to a s o l u t i o n o f impure Hg(BALH) i n p y r i d i n e r e s u l t s i n an increase i n c o n d u c t i v i t y (35). Stability constants f o r formation o f the neutral and i o n i c complexes i n water have r e c e n t l y been determined by potentiometric t i t r a t i o n (40), and the very high values c o n t r i b u t e to the e f f e c t i v e n e s s of B r i t i s h a n t i - L e w i s i t e as an a n t i d o t e . 2


2

Hg

2 +

+ BALH " * ±

Hg(BALH)

2

Hg(BALH) + BALH *

Log Κ = 25.74 ± 0.45

[Hg(BALH) ] "

2

2

Log Κ = 8.61 ±

2

0.10

Organomercury d e r i v a t i v e s o f BALH3 may be obtained by r e a c t i o n with phenylmercuric acetate i n water and methyl mercuric acetate i n benzene (35). 2RHg0 CMe + BALH^ + (RHg) BALH + 2MeC0 H 2

2

2

Infrared and Raman spectra o f these complexes and other organomercury t h i o l a t e s i n d i c a t e monomeric s t r u c t u r e s i n the s o l i d s t a t e as v(Hg-S) values (326-388 cm" ) are i n the region expected f o r l i n e a r c o o r d i n a t i o n f o r mercury, and coincidence of i n f r a r e d and Raman values i n d i c a t e absence o f a centre o f symmetry a t mercury (Figure 5,6) (35), thus excluding dimeric s t r u c t u r e s s i m i l a r to t h a t formed by r e l a t e d PhHg(II) alkoxides i n benzene (Figure 7) (41). 1H NMR spectroscopy i s p a r t i c u l a r l y useful f o r c h a r a c t e r i z a t i o n o f organomercury compounds. Thus, (MeHg) BALH has j ( l H - l " H g ) 169 Hz f o r the NeHg(II) group, and PhHg(II) t h i o l a t e s have J(orthOH-199Hg) 144-158 Hz and J(orthOH-meta ) 6-8 Hz (35). The complexes (RHg) BALH (R=Me,Ph) are i n s o l u b l e i n water but d i s s o l v e i n p y r i d i n e and dimethylsulphoxide, and the r e l a t e d t h i o l a t e of lower molecular weight, PhHgSCH CH 0H, i s s o l u b l e and monomeric i n chloroform. However, organomercury t h i o l a t e s formed from n a t u r a l l y o c c u r r i n g t h i o l s i n vivo are l i k e l y to be water s o l u b l e , e . g . the L - c y s t e i n e complexes MeHgSCH2CH(NH3)C0 .H 0 and PhHgSCH CH(NH )C0 contain hydrop h i l i c z w i t t e r i o n i c groups and c r y s t a l l i z e from aqueous ethanol (12,36). Thus, displacement o f b i o l o g i c a l t h i o l ligands with BALH3 i s expected to form more l i p i d s o l u b l e complexes, as suggested by B e r l i n et_aj_. (20), and may account f o r higher concentrations o f mercury i n b r a i n t i s s u e of animals administered BALH3 a f t e r i n j e c t i o n o f organomercury compounds when compared 1

2

H

2

2

2

2

2

3

2

2



CANTY

Mercury Compounds

R

Hg

SR

Figure 5.

R

Hg

SCH

R

Hg

SCH

2

CH OH 2

Figure 6.

R 0 Ph

Hg

Hg

Ph

0 R Figure 7.


ORGANOMETALS

332

AND

ORGANOMETALLOIDS

with concentrations i n the absence of BALH3 treatment. It was found that (PhHg^BALH decomposes at ambient temperature i n acetone, benzene, and methanol to form Ph2Hg (30,35) (Table I). (PhHg) BALH + Ph Hg + Hg(BALH) 2

2


Table I Decomposition o f Some Phenylmercury (II)

Complex

Solvent

(PhHg)oBALH (PhHg)2BALH PhHg(H3cyst) PhHg(H3pen) (PhHg)2(H cyst)-H20 (PhHg)2H2Pen

acetone benzene benzene benzene benzene benzene

2

Thiolates

Y i e l d o f Ph Hg(%) 2

96 100 55 81 44 43

From references 35,36. Suspensions a t ambient temperature were s t i r r e d magnetically for seven days. Ph2Hg was i s o l a t e d as a pure s o l i d from the f i l t r a t e . b Y i e l d o f Ph Hg based on ' P h . H 3 c y s t = SCH CH(NH3)C0 ; H c y s t = SCH CH(NH2)C0 ; s i m i l a r l y f o r HSCMe2CH(NH )C0 , DL-pen i ci11 ami ne. 1

2

c

2

3

2

2

2

2

2

I f t h i s r e a c t i o n occurs i n vivo i t may a l s o c o n t r i b u t e to r e d i s t r i b u t i o n of mercury, and to i n d i c a t e whether PI^Hg formation may be a general b i o l o g i c a l r e a c t i o n i n the absence of BALH3 s e r i e s o f PhHg(II) complexes of s u l p h u r - c o n t a i n i n g ami no acids was prepared and t h e i r s t a b i l i t i e s studied (36). The complexes were synthesized by r e a c t i o n of phenylmercuric acetate with the amino acids i n aqueous e t h a n o l , e . g . a

2PhHg0 CMe + ftycyst ·* (PhHg) (H cyst)-H20 + 2MeC02H 2

2

2

The D L - p e n i c i l l a m i n e complexes have been prepared by other workers, but the s t a b i l i t y o f the complexes toward decomposition had not been studied (16). The amino a c i d complexes were found to decompose i n benzene to form Ph2Hg (Table I). The importance of these r e a c t i o n s , and decomposition o f (PhHg)2BALH, i s d i f f i c u l t to assess as they are s o l v e n t dependent and rates o f decomposition v a r y , e . g . (PhHg)2BALH and amino a c i d complexes may be r e a d i l y prepared i n


20.

Mercury Compounds

CANTY

333

aqueous s o l u t i o n , they decompose slowly i n benzene, and when PhHgi^CMe and BALH3 ethanol immediate p r e c i p i t a t i o n occurs and PI^Hg may be obtained from the f i l t r a t e on f i l t r a t i o n . I f Ph Hg i s formed i n vivo then the b i o l o g i c a l behaviour o f Ph Hg i s o f i n t e r e s t as phenylmercury compounds, e . g . PhHg0 CMe, are s t i l l widely used i n a g r i c u l t u r e and medicine. I t has been reported t h a t Ph Hg i n " s c a r c e l y d e t e c t a b l e " concentration formed by degradation o f p h e n y l mercuric acetate (formerly contained i n d e r e l i c t s t e e l drums), was s u f f i c i e n t l y t o x i c to k i l l f i s h w i t h i n a few hours i n the Boone R e s e r v o i r , Tennessee V a l l e y (43). a

r

e

r

e

a

c

t

e

d

l

n

2

2

2


2

Biological

Behaviour of

Piphenylmercury

Diphenylmercury has q u i t e d i f f e r e n t p h y s i c a l and chemical p r o p e r t i e s than PhHg(II) compounds, e . g . i t i s a neutral nonp o l a r molecule i n s o l u b l e i n water but s o l u b l e i n organic solvents and i s thus expected to be l i p i d s o l u b l e (44), and i n c o n t r a s t to PhHg(II) compounds (45,46,47) i t i n t e r a c t s o n l y weakly with donor molecules (48,49,50). S i m i l a r l y , Me Hg does not form complexes (45) but MeHg(II) forms s t a b l e complexes, e . g . [MeHgL] with p y r i d i n e (51,52), 2 , 2 * - b i p y r i d y l (51,52,53» 54), and 1,10-phenanthroline T52,53). In d i s t r i b u t i o n and metabolism s t u d i e s we have i n j e c t e d ethanol s o l u t i o n s o f mercuric c h l o r i d e , phenylmercuric a c e t a t e , o r Ph Hg i n t r a p e r i t o n e a l l y i n t o r a t s (55,56). The r a t s were s a c r i f i c e d a t i n t e r v a l s ranging from 20 min. to 7 days and samples of b l o o d , b r a i n , l i v e r , kidney, muscle, f a t , and spleen were analysed f o r mercury. In another s e r i e s o f experiments faecal and u r i n a r y e x c r e t i o n was monitored f o r several days after injection. During the f i r s t few days a f t e r i n j e c t i o n , u r i n a r y e x c r e t i o n o f mercury was much higher f o r the diphenylmercury-injected r a t s than f o r the phenylmercuric acetate o r mercuric c h l o r i d e i n j e c t e d r a t s , with mercuric c h l o r i d e having the lowest rate o f excretion. Faecal e x c r e t i o n was s i m i l a r f o r the three compounds, with phenylmercuric acetate being more r a p i d l y excreted (Table II). Analyses o f blood and t i s s u e s f o r t o t a l mercury i n d i c a t e d that a f t e r i n i t i a l marked d i f f e r e n c e s i n b r a i n and f a t t y t i s s u e c o n c e n t r a t i o n s , the d i s t r i b u t i o n o f mercury f o r Ph2Hg resembled those o f the other compounds a f t e r 1 day, but concentrations were g e n e r a l l y lower than f o r the other compounds (55,56). The lower concentrations are explained by the more r a p i d e x c r e t i o n o f mercury from Ph Hg. During the f i r s t hour a f t e r i n j e c t i o n mercury from Ph2Hg accumulated a t a higher c o n c e n t r a t i o n i n the b r a i n than from the other compounds, but a f t e r 6 hours these concentrations had decreased c o n s i d e r a b l y (55_,5(5). The concentration of mercury i n f a t t y t i s s u e was 10-20 times higher f o r diphenylmercury2

+

2

2


334

ORGANOMETALS

AND

ORGANOMETALLOIDS

Table II Urinary and Faecal E x c r e t i o n o f Mercury from Rats w i t h i n Two Days o f I n j e c t i o n

HgCl

PhHg0 CMe

2

2


Percentage o f dose

2.5 5.2 7.7

Urinary E x c r e t i o n : Faecal E x c r e t i o n : Urinary + Faecal :

2.2 4.5 6.7

4.8 12.2 17.0

8.0 8.4 16.4

Ph Hg 2

excreted

30.5 5.6 36.1

38.3 3.6 41.9

From reference 56. Analyses f o r t o t a l mercury, as described elsewhere (55). Two r a t s were i n j e c t e d i n t r a p e r i t o n e a l l y with each compound, dose 248 mg mercury, a l l r a t s o f weight 160 g.

i n j e c t e d r a t s a t 20 min. a f t e r i n j e c t i o n , but then r a p i d l y dropped to values s i m i l a r to the other mercury compounds (Table III). The much higher c o n c e n t r a t i o n of mercury i n b r a i n and f a t t y t i s s u e immediately a f t e r Ph Hg i n j e c t i o n i s c o n s i s t e n t with d i s t r i b u t i o n o f mercury as, Ph Hg, and t h i s was confirmed by t h i n - l a y e r chromatography. A sample o f f a t t y t i s s u e taken from a diphenylmercury-injected r a t 20 min. a f t e r i n j e c t i o n was blended with benzene using a small Waring blender, and t h i n l a y e r chromatography showed the presence of diphenylmercury ( u l t r a v i o l e t i r r a d i a t i o n ) ; the s i l i c a gel o f the p l a t e a t the Rf value o f Ph Hg contained 5.19 mg. o f Hg/g o f s i l i c a gel compared with 0.15 mg/g f o r s i l i c a gel at lower Rf value on the same p l a t e . It has been e s t a b l i s h e d that phenylmercury i s degraded to inorganic mercury i n a few days i n r a t s (57,58,5£,60,61). Daniel e t a l . (60) represent t h i s breakdown as 2

2

2

C

6 5 H

H g +

+

H +

C

6 6 H

+

H

g

2

+

A s i m i l a r breakdown may occur f o r Ph Hg, presumably v i a PhHg(II), as the i n i t i a l high concentrations o f mercury i n b r a i n and f a t t y t i s s u e f a l l to values s i m i l a r to that obtained with the other compounds a f t e r 6 h r . and 1 h r . , r e s p e c t i v e l y . Thus, i f Ph Hg i s formed i n vivo i t s b i o l o g i c a l e f f e c t s are d i f f i c u l t to evaluate as i t i s more r a p i d l y excreted than PhHg(II) and apparently broken down by the body, but has a q u i t e d i f f e r e n t i n i t i a l d i s t r i b u t i o n . However, i t i s o f i n t e r e s t to note that although mercury vapour i s o x i d i z e d to Hg(II) i n c a . 30 sec. i n blood t h i s i s s u f f i c i e n t time f o r mercury (from vapour) to 2

2


20.

CANTY

Mercury Compounds

335

Table III Concentration o f Mercury i n Brain and Fatty T i s s u e s o f Hooded Wistar Rats Injected I n t r a p e r i t o n e a l l y with Mercury Compounds


Time

Brain

Dose o f 6 mg. o f Hg/kg o f r a t . mercuric c h l o r i d e 20 min. (2) 0.16 ± 0.02 1 h r . (2) 0.33 ± 0.07 6 h r . (2) 0.16 ± 0.01 1 day (2) 0.24 phenylmercuric acetate 20 min. (2) 0.14 ± 0.04 1 h r . (2) 0.47 ± 0.03 6 h r . (2) 0.9 ± 0.3 1 day (2) 0.65 ± 0.02 diphenyImercury 20 min. (2) 0.9 ± 0.2 1 h r . (2) 0.7 ± 0.2 6 h r . (2) 0.26 ± 0.01 1 day (2) 0.20 ± 0.03

Fat

A.

Dose of 1.5 mg. of Hg/kg o f r a t . mercuric c h l o r i d e 20 min. (1) 0.04 phenylmercuric acetate 20 min. (1) 0.01 diphenylmercury 20 min. (1) 0.3

10.5 4.8 3.4 15.7

+ + + +

2.8 2.1 1.3 5

5 4.4 4.7 3.5

± + + +

2 1.2 0.2 0.3

147 10.4 10.1 3.6

±13 + 3.2 + 3.4 + 0.2

B.

2.34 0.9 27.8

From reference 56_. Recorded as yg o f Hg/g t i s s u e , wet weight, and the range o f values i s i n d i c a t e d . The number o f r a t s i n each category i s given i n parentheses with the time. achieve an c a . t e n - f o l d higher accumulation i n the b r a i n than from i n o r g a n i c mercury poisoning (27,62) leading to higher t o x i c i t y o f mercury vapour. Acknowledgements I thank the National Health and Medical Research Council and the Commonwealth Development Bank f o r f i n a n c i a l support, and my co-workers, R. Kishimoto and R. S. Parsons, f o r t h e i r c o n t r i b u t i o n s to work reviewed here.


336

organometals and organometalloids

Literature 1. 2. 3.


4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.

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Received August 22, 1978.


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