Determination and metabolism of dithiol chelating agents: X. In humans, meso-2,3-dimercaptosuccinic acid is bound to plasma proteins via mixed disulfide formation.
meso-2,3-Dimercaptosuccinic acid (DMSA) is orally effective for the treatment of chronic lead intoxication in humans. Earlier studies have shown that the majority of DMSA, given p.o. to normal humans, is excreted in the urine as mixed disulfides with L-cysteine. We have developed an assay for the determination of DMSA that has made possible the determination of the form of DMSA in blood and plasma. After p.o. administration of 10 mg DMSA/kg to four normal young men, no unaltered DMSA (unaltered DMSA is the unbound, parent compound; total DMSA consists of unaltered DMSA plus oxidized (disulfide) DMSA and is determined after reduction with dithiothreitol) was found in the blood over an 8-hr period. Only after treatment of blood or plasma with the disulfide-reducing agent, dithiothreitol, was DMSA detected. This indicates that DMSA is in disulfide linkage with plasma proteins and/or non-protein sulfhydryl compounds. Most of the DMSA in the plasma (92-95%) was found to be bound to plasma proteins, mainly albumin. The remaining DMSA may be bound to small molecular weight (less than 10,000 MW) nonprotein sulfhydryl compounds such as cysteine. Plasma protein appears to serve as a depot and reservoir of DMSA, which can exchange for cysteine. The urinary excretion of unaltered DMSA and DMSA mixed disulfides with L-cysteine suggests that this exchange takes place at the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Maiorino
R M
RM
Department of Molecular and Cellular Biology, University of Arizona, Tucson.
Akins
J M
JM
Blaha
K
K
Carter
D E
DE
Aposhian
H V
HV
D000284:Administration, Oral; D000328:Adult; D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D004113:Succimer / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics; D013438:Sulfhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology*
D001798:Blood Proteins; D002614:Chelating Agents; D013438:Sulfhydryl Compounds; D004113:Succimer