Dallas L. Rabensteln University of Alberta Edmonton, Alberta. Canada
I
The IChemistry of Methylmercury
Methylmercury, CH3Hg(II),is one of the most toxic forms of mercury, causing irreversible damage to the central nervous system. Methylmercury, CH3Hg(II), is one ofthe most toxic forms of mercury, causing irreversible damage to the central nervous svstem. Laree scale outbreaks of methvlmercurv ooisonine gave occurrzd in various parts of the world. In japan, poisonings in the Minimata Bav and Niieata areas resulted from consumption of methylmercury-contaminated fish. The methylmercury was traced to waste water from plastics industries using inorganic mercury compounds as catalysts. In Irao. massive noisonines have resulted from the consumtion of 11;ead made from wheat seed treated with methyl and ethvlmercuw funairides ( I I. However, it was the discovery in the i960's ofmeth;lmercury in fish taken from waters havingno known source of methvlmercury that caused widespread concern about a genernl-threat topublic health. Subsequent research revealed h t h enzymaticand nonenzymatic pathways by which microorganisms in bottom redimenu can methylate inowanic and metallic mercury (24).These findings provided a st&ulus for research on the chemistry and biochemistry of methylmercury. Althoueh the nature of the damaee to cells of the central nervous sistem is still not known at &e molecular level, many asoects of the behavior of methvlmercurv in bioloeical - svstems . are now understood in terms of its chemistry. In this article, an overview of methvlmercurv . poisoning . - and its treatment is presented. The emphasis is on relating the solution chemi s t of ~ CH:,He(lIJ to what is known about its behavior in humans andotberspecies.
-
The Chernlstry of CHsHg(ll)
T o a laree extent. the coordination chemistm of CH.He(I1) determines its behavior in biological systems.;rhe co&&ation chemistm of CHqHe(II) - - . has been reviewed recentlv. (5).. and only the key points will be mentioned here. A characteristic of the coordination chemistry of C H R H ~ I I ) is its strong tendency to complex with a coordination =her of one (6). The formation constants of selected complexes of interest with respect to CHzHg(I1) in biological systems are given in Tahle 1.The formation constants indicate that sulfhydryl groups are the favored binding sites in biological lieands. However, to estahlish relative affinity orders for the other binding sites, the effect of competing reactions must he accounted for; at low pH, protons compete with CHzHg(I1) for the ligand while a t high pH hydroxide ions compete with ligand for CHzHg(I1). This is illustrated in Figure 1hy the pH deoendence of the fractional concentration of the (:~~~g(l~)-acet~lgl~cine n~mplex.Also shown are fractional concentration curves for theother CH:,He(lIl - - . . and acetvlalv.-. cine species. The effect of comoetine reactions can be accounted for most easily by using pH-dependent conditional formation con-
'
The conditional formation constant is defined by the reaction CH3Hgr, + Lr,, a CHsHgL and is calculated from the thermodynamic formation eonstant and equilibrium constants for the acid-base equilibria of the ligand and methylmercury. For details, see Laitinen, H. A,, and Harris, W. E., Chem. Anal., McGraw-Hill, Inc., 1975, p. 194. 292 1 Journal of Chemical Education
stants.' Conditional formation constants for the complexes listed in Table 1are plotted as a function of pH in Figure 2. The conditional formation constants show the relative affinities of the potential binding sites for CHaHg(I1) to be strongly pH dependent, with the nucleic acid bases uracil and thymine and the imidazole group of histidyl residues the most important binding sites after the sulfhydryl group. Although the thermodynamic stability of CH3Hg(II)sulfhydryl complexes is large, they are extremely labile. In the CH3Hg(II)-glutathione system, ligand exchange can occur by three processes C H ~ H ~ S+GGS-
CHsHgSG
SCH~H~SG + GS(1) k-1
+ H+ +CH3Hg++ GSH kl
(2)
k-l
where GSH and GS- represent the protonated and deproto- 600 nated forms of glutathione; k l = 5.8 X lo8 M-Is-' ,k 2-M-L-1, and k - ~= 5.1 x lo9 M-'s-' (7). Reaction 1is himolecular and involves a nucleophilic ligand Table 1. Formatlon Constants of Methylmercury Complexes Ligand
PK* of log Kt Ligand' Ref.
CDmplex
H
I
Acetylglycine
CH,CNCH,COJigC& II
Methylamine
CH.,HgNH&H,
6
+
2.68
3.40
(5)
7.57
10.81
(5)
8.93'
(25)
H\
I
+, , , Uridine Chloride Hydroxide
I
NH;L
Glutathione
CHgHgCI
CHRgOH
15.9
II
5.25 9.37
(6) (6)
pH Figure 1. Fractional concentration of the CH$Hg+-acetylgiyclne complex and of the other me~ylmercuryand acetyiglycine species In a 0.010 Mmethyimercury. 0.010 Macetyigiycins mixture as a function of pH. A, HL: 8. L-; C, C H & L ; D, CHSH~+;E, C ~ H ~ O F, H ;[ C H ~ H ~ ) ~ O H + .
mulate in the kidnev. the b e e t orean for inoreanic mercurv. Little is found in the'brain dLe to ;he inabilitiof ~ ~ ( 1a&1 ) its biocomolexes to cross the blood-brain barrier. Followine i n h a l a t i o n h ~vapor, ~ the pattern of distribution ofmercur; throurhout the body is similar to that followina ineestion of ~ ~ ( 1 1with 7 , the important exception of the biain: A small amount of the inhaled vapor pxisu in the blood as HpO, which readily diffuses across the blood-brain harrier. In the brain, it is oxidized to HEW)which then damages cells of the nervous of distribution and symptoms following system. The ingestion of phenyImercury and mercurial diuretics are similar to those of Hg(I1) due to their rapid biotransformation to Hg(I1). In contrast, however, the Hg-C bond in CHsHg(I1) and other short chain alkvlmercurials is stable in hioloeical media, resulting in a diffirent pattern of distribution a i d a different effect on the bodv. Because of its l i ~ i dsoluhilitv. C H ~ H ~ ( Ireadily I) crosses the blood-brain b a k e r and act;: mulates in the brain, the target organ in methylmercury poisoning. Biotransformation to Hg(I1) plays a role only in the excretion of CH3Hg(II). The general behavior of CHsHg(I1) in humans is shown schematically in Figure 3. Because of the high affinity of deprotonated sulfhydryl groups for CHsHg(II), it generally is assumed that the methvlmercuw in foodstuffs, particularly fish, is in the form of complexes i f cysteine-containing peptides and proteins. Once incested, it is very efficiently ahsorbed from the gastrointest&al tract into the blood stream. The form in which i t is absorbed is not known, but there are several possibilities, including lipid-soluble CH3HgC1(8). In the stomach, CH3Hg(II) is in a medium of low pH (1.5-2.5) and hieh chloride concentration. The relative conditional formacon constants for sulfhydryl and chloro complexes predict that, under these conditions, a sizeable fraction of the Table 2. Red Blood CelllPlasma Ratlo. Whole BioodlBraln Ratio, and Biological Half Time for Various .Specles -.-
-
RBCIPiamsa Ratiod
Species
I
I
I
1
5
P
I
I
I
I
I
pH Fiaure 2. Loaarlthm of the conditional formation constant versus pH for the C ~ H
