Chelation in Metal Intoxication￢ﾀﾔprinciples and Paradigms

Home , Deferiprone, Dimercaptosuccinic acid

Journal of Trace Elements in Medicine and Biology 31 (2015) 260–266

Contents lists available at ScienceDirect

Journal of Trace Elements in Medicine and Biology

jo urnal homepage: www.elsevier.com/locate/jtemb

Review

Chelation in metal intoxication—Principles and paradigms

a b,∗ c d

Jan Aaseth , Marit Aralt Skaug , Yang Cao , Ole Andersen

Innlandet Hospital Trust, Kongsvinger Hospital Division, Kongsvinger, Norway

Faculty of Public Health, Hedmark University College, 2418 Elverum, Norway

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

Department of Science, Systems and Models, Roskilde University, Roskilde, Denmark

a r t i c l e i n f o a b s t r a c t

Article history: The present review provides an update of the general principles for the investigation and use of chelating

Received 30 January 2014

agents in the treatment of intoxications by metals. The clinical use of the old chelators EDTA (ethylene-

Accepted 6 October 2014

diamine tetraacetate) and BAL (2,3-dimercaptopropanol) is now limited due to the inconvenience of

parenteral administration, their own toxicity and tendency to increase the neurotoxicity of several metals.

Keywords:

The hydrophilic dithiol chelators DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercapto-

DMSA

propanesulphonate) are less toxic and more efﬁcient than BAL in the clinical treatment of heavy metal

DMPS

poisoning, and available as capsules for oral use. In copper overload, DMSA appears to be a potent anti-

Deferiprone

Deferasirox dote, although -penicillamine is still widely used. In the chelation of iron, the thiols are inefﬁcient, since

Deferoxamine iron has higher afﬁnity for ligands with nitrogen and oxygen, but the new oral iron antidotes deferiprone

and desferasirox have entered into the clinical arena. Comparisons of these agents and deferoxamine

infusions are in progress. General principles for research and development of new chelators are brieﬂy

outlined in this review.

Contents

Introduction ...... 260

Chemical principles for chelation therapy ...... 261

Metal ions and chelating ligands—principles of interactions...... 261

Competition during ligand exchange ...... 261

New agents and paradigms in clinical treatment of metal poisonings ...... 262

DMSA (Succimer) and DMPS (Dimaval)—oral chelation therapy ...... 262

Clinical use and misuse of DMSA and DMPS ...... 262

Inappropriate or obsolete use of EDTA ...... 263

-Penicillamine and trientine—old but not outdated drugs? ...... 264

Deferiprone and deferasirox—oral iron chelators...... 264

Conclusion ...... 265

Conﬂicts of interest ...... 265

Appendix A. Supplementary data ...... 265

References ...... 265

Introduction

British anti-Lewisite, BAL (2,3-dimercaptopropanol), was devel-

Chelating agents are of great importance in the treatment of oped by a British group as a potent antidote against the poisonous

intoxications and overload with metals. The classical antidote Lewisite, a vesicant arsenical gas, during the Second World War

[1]. The ﬁrst clinical use of BAL was in intoxications due to organic

arsenical drugs for treating syphilis [2]. EDTA (ethylenediamine

∗

tetraacetate), another chelator, was introduced into clinical use

Corresponding author. Tel.:+47 41424584; fax: +47 62430001.

E-mail address: [email protected] (M.A. Skaug). around 1950 initially as antidote in lead intoxication [3]. However,

http://dx.doi.org/10.1016/j.jtemb.2014.10.001

J. Aaseth et al. / Journal of Trace Elements in Medicine and Biology 31 (2015) 260–266 261

the clinical roles of BAL and EDTA as metal antidotes today are reach equilibrium, i.e. ML, the chelate formed, should be continu-

limited due to the inconvenience of parenteral administration, ously removed from the equilibrium, for instance via urine.

their own toxicity and the tendency to redistribute toxic metals Some crucial qualities of a chelator to deduce its clinical effec-

into the brain [4]. tiveness may be summarized as follows:

In the treatment of metal storage diseases, chelating agents are

of great importance. In 1956, Walshe [5] reported his treatment of

- appropriate pharmacokinetics;

Wilson’s disease patients with d-penicillamine (dimethyl cysteine)

- high afﬁnity towards the toxic metal;

to enhance copper excretion. He later used trientine (triethylene

- low toxicity;

tetramine) to treat patients who could not tolerate penicillamine

- forming chelate with rapid elimination or detoxiﬁcation.

[6]. Another progress was the demonstration of the effect of defer-

oxamine in the treatment of transfusional siderosis [7]. More

With regard to the chemical stability of a therapeutic chelate, it

recently, orally administered iron chelators, deferiprone or des-

is of interest that the ﬁrst approximation of the afﬁnity of a ligand

ferasirox, have been developed [8]. The efﬁciency of the relatively

(L) towards a toxic metal can be deduced from the Hard-Soft-Acid-

new chelating agents, i.e. DMSA (meso-2,3-dimercaptosuccinic

Base concept, as discussed previously [9,10] and below.

acid) and DMPS (d,l-2,3-dimercapto-1-propanesulfonic acid) in

poisonings with arsenicals and several other heavy metal com-

Metal ions and chelating ligands—principles of interactions

pounds, appears to be better than that of the classical chelators

BAL and EDTA.

Lewis [11] deﬁned an acid as an electron pair acceptor, and

The aim of this overview is to outline the chemical and biological

a base as an electron pair donor. According to this terminology,

principles of the action of chelating agents, and criteria of searching

all the positively charged metal ions can be classiﬁed as acids,

new potent agents. Clinical use and misuse of chelation therapy are

since they may act as electron acceptors. The formation of a sol-

also discussed.

vated (hydrated) metal ion is in fact the formation of a complex.

Here, the water molecule acts as an electron donor, and H2O can

Chemical principles for chelation therapy

thus be described as a Lewis base. Many other oxygen-containing

agents can be described as Lewis bases as well. In aqueous solutions,

In general, the aim of chelation treatment is to remove toxic

metal ions exist in solvated forms, and chelation or complexation

metal ions from the vulnerable sites in the critical organs. This

involves that water in the solvated shell is replaced by another

requires that the chemical afﬁnity of the complexing agent for the

ligand (another Lewis base) to give a metal complex.

metal ions is higher than the afﬁnity of the metal ions for the sen-

Lewis acids and bases can be classiﬁed as hard or soft ones. A hard

sitive biological molecules. Accordingly, chemical assessment of

metal ion is one that retains its valence electrons very strongly and

the stability constants of the metal-complexes formed may give

has small size and high charge. In contrast, a soft ion is relatively

an indication of a chelating agent’s efﬁcacy. In simple cases to form

large and does not retain its valence electrons ﬁrmly. Examples of

a 1-to-1 complex between metal ion and chelator, the interaction + 2+ 3+

hard metal ions are Li , Mg , and Fe . Soft metals include copper(I),

can be described by the equilibrium:

mercury(II), arsenic, polonium(II) and platinum(II) [12].

[ML] The hardness/softness characteristics of the electron donor lig-

K = , (1)

1 M L ands and the metal ions determine the stability of metal complexes

[ ] [ ]

and chelates, as discussed by Pearson in his works on the Hard-Soft-

where K1 represents the stoichiometric stability constant, M Acid-Base theory [13]. As a rule, the formation of stable complexes

represents the solvated metal ion, L represents a chelator, and the results from the interaction of hard bases with hard acids, or soft

square brackets denote concentrations (or activities) of interacting bases with soft acids. Typical examples of hard bases contain oxygen

species at equilibrium. as donor atom, whereas nitrogen can be classiﬁed as a hard-to-

Presumably, the formation of the 1-to-1-complex between the intermediate donor atom. Thus, Fe(II) as well as Fe(III) will interact

monothiol penicillamine and the monovalent compound methyl with oxygen or nitrogen in biological ﬂuids, e.g. in the synthesis

mercury in aqueous solutions can be described by this simple equa- or formation of molecules such as heme or hemoglobin. On the

tion. However, chelating agents may contain several coordination other hand, easily polarized ligands containing sulfur or selenium

groups. Consequently, the calculations of equilibrium concentra- are classiﬁed as soft groups, forming stable complexes with mer-

tions, even in simple aqueous solutions, could be much more cury, polonium, arsenic, and with copper(I) and lead. The bonding

complicated. In addition, when complexation occurs in body ﬂuids, in hard-hard complexes is largely electrostatic, e.g. the iron-oxygen

M and L can enter into numerous side reactions, and free concen- bond, whereas soft-soft complexes have bonds with a predomi-

trations of L and M in body ﬂuids and tissues are consequently nantly covalent nature, e.g. the mercury thiol bond. Mercury, as

smaller than the total concentrations [Lt] and [Mt] of the interacting well as arsenic, has strikingly high electronegativity, viz. about 2.0

species. This has been taken into account by introducing the so- in Pauling units, and consequently high tendency to be engaged in

called conditional stability constant or effective stability constant, covalent bonding to carbon as well as to sulfur, compared to other

Keff [9]. metals. This explains the existence of a large number of organomer-

Theoretically, the chelatable or mobilizable metal fraction, [ML], curials and organoarsenicals.

is determined by the effective stability constant Keff and the tissue

concentration [Lt] of the chelating agent, as is seen by rearranging

Competition during ligand exchange

Eq. (1) as

ML Because of the availability of numerous small biological lig- [ ] =

K L (2)

effx [ t] ands, the concentrations of “free” toxic metals are often very low

[Mt]

in biological systems. Thus, endogenous low molecular weight

It is evident that a high tissue concentration [Lt], and thus a compounds such as cysteine, arginine, glutamate, citrate and glu-

signiﬁcant concentration of ML, can only be achieved by using tathione, as well as proteins are metal-binding agents. An example

chelators with relatively low toxicity. Furthermore, to achieve an of an endogenous multidentate structure of great biological signif-

efﬁcient chelation treatment, the chelation reaction should never icance is the porphin core of hemoglobin, which encapsulates Fe , Download English Version: https://daneshyari.com/en/article/1226402

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