Chelation of cadmium without increased renal cadmium deposition.

Abstract

Cadmium (Cd) is mainly accumulated in liver and kidney bound to metallothionein (MT) and excreted very slowly from the body. In chronic exposure, Cd is gradually transported from liver to kidney; the renal toxic effects appear when renal Cd concentration exceeds the critical concentration. In order to prevent the Cd-induced renal disease, it is important to control the movement of Cd to the kidney and its renal deposition. However, the chelation of Cd from liver is difficult because of the high affinity of intracellular MT for Cd. A number of chelating agents containing both carboxyl and thiol groups were able to mobilize and excrete Cd more easily in a short time (1/2 hr) after Cd exposure than longer times (24 hr), after MT synthesis. The renal deposition of Cd increased on BAL (2,3-dimercaptopropanol) treatment a short time (1/2 hr) after Cd exposure. However, it was observed that if BAL was administered 24 hr after Cd exposure, it could mobilize Cd from hepatic MT and increase the biliary excretion of Cd without any increase in renal Cd concentration. Studies using a number of structurally related thiols (mono-, di-and trithiols) showed that the major structural requirement for in vivo chelation of Cd from intracellular MT were the vicinal thiol groups on an aliphatic chain, and lipophilicity. BAL was the most effective of all the compounds studied and it did not mobilize Cd to the kidney, when most of the intracellular Cd was bound to MT. Furthermore, a delayed treatment with BAL or DTPA (diethylenetriamine pentaacetic acid) after synthesis of MT resulted in an increase in fecal or urinary excretion of Cd in rat model experiment. The injection of DTPA in combination with BAL was more effective in decreasing the concentration of Cd and MT in liver and kidney from rats chronically exposed to Cd than injection of BAL alone. Since DTPA cannot enter the cell, it may be acting extracellularly in removing the Cd. The results of these studies suggest that the specific intracellular binding of Cd to MT is an important factor in protecing kidney, the critical organ, in the effective chelation of Cd by BAL.The development of an effective chelation therapy for cadmium (Cd) has been extremely difficult because of the special features in the pharmacokinetics and toxicity of Cd compounds. Unlike other metals, Cd has an unusually long biological half-time in human and is excreted very slowly from the body (1). After absorption from the respiratory and gastrointestinal tracts, Cd is mainly accumulated in liver and kidney bound to metallothionein (MT), a low molecular weight sulfur-rich intracellular protein (2,3). The low excretion of Cd from the body may be closely related to its specific intracellular binding to MT. Although acute and chronic Cd poisonings in humans are not common, there are isolated cases of chronic Cd poisoning in workmen and people liv-

Chelation in Metal Intoxication XXIX: α‐Mercapto‐β‐aryl Acrylic Acids as Antidotes to Mercury (II) Toxicity

“…However, since no change in renal MT content was observed upon treatment with DMS, MPA, MHA and MMA, it may be suggested that neither these thiol compounds synthesized any additional renal MT nor the renal MT once induced by Hg was dependent on the Hg status of the MT. The decrease in renal and hepatic MT accompanied by lowering in their Hg levels on treatment with MFA are not in agreement with the reported mode of action of MFA (Giroux & Lachmann 1983). Contrary to the present finding, Giroux & Lachmann (1983) found increased renal MT and Hg burden which might be due to the difference in two experimental protocols.…”

“…However, DMS seems to remove Hg also via kidneys and to be the most effective owing to the presence of two adjacent-SH groups in the compound (Cherian 1984;Sharma et al 1987). However, DMS seems to remove Hg also via kidneys and to be the most effective owing to the presence of two adjacent-SH groups in the compound (Cherian 1984;Sharma et al 1987).…”

“…However, DMS seems to remove Hg also via kidneys and to be the most effective owing to the presence of two adjacent-SH groups in the compound (Cherian 1984;Sharma et al 1987). Contrary to the present finding, Giroux & Lachmann (1983) found increased renal MT and Hg burden which might be due to the difference in two experimental protocols. However, since no change in renal MT content was observed upon treatment with DMS, MPA, MHA and MMA, it may be suggested that neither these thiol compounds synthesized any additional renal MT nor the renal MT once induced by Hg was dependent on the Hg status of the MT.…”

“…Nuclear-mitochondria1 Cytosolic Treatment Kidnev fraction fraction different a-mercapto-P-aryl acrylic acids and DMS suggest that the compounds act by a mechanism characteristic of chelating agents, that is, mobilization of the metal as their complexes through sulfhydryl group and that the biliary route is major one for the elimination of Hg-SH moiety. However, DMS seems to remove Hg also via kidneys and to be the most effective owing to the presence of two adjacent-SH groups in the compound (Cherian 1984;Sharma et al 1987). The decrease in the renal burden of Hg as reflected by its lowering mainly in the renal cytosolic fraction upon treatment with MFA, MPA MHA and MMA without significant increase in the urinary excretion of Hg, indicates redistribution of Hg following displacement of renal MT bound Hg.…”

“…1980;Aposhian 1983;Kachru & Tandon 1986;Khandelwal et al 1988). The a-mercapto-P-(Zfuryl) acrylic acid (MFA), also a thiol chelator, is believed to act by inducing metallothionein (MT) biosynthesis capable of binding Hg, rendering it biologically inactive (Giroux & Lachmann 1983). However, it has not been clarified whether MFA acts solely through tissue MT induction or in addition, behaves as a true metal chelator that is, mobilizing Hg out of the body.…”