Mobilization of lead in mice by administration of monoalkyl esters of meso-2,3-dimercaptosuccinic acid.
The following six monoalkyl esters of meso-2,3-dimercaptosuccinic acid (DMSA) were synthesized and evaluated for relative activities in mobilizing lead from kidneys and brains of lead-bearing mice: n-propyl (Mn-PDMS), i-propyl (Mi-PDMS), n-butyl (Mn-BDMS), i-butyl (Mi-BDMS), n-amyl (Mn-ADMS) and i-amyl meso-2,3-dimercaptosuccinate (Mi-ADMS). DMSA was used as a positive control. When each was administered intraperitoneally (i.p.) as a single dose of 2.0 mmol/kg, DMSA lowered the kidney lead concentration 52%, while the monoesters effected reductions of 54-75%. Mn-ADMS was toxic at this dose. DMSA lowered the brain lead level 20% when given as a single dose, while the monoesters conferred reductions of 64-87%. When given as 5 daily i.p. injections at 0.5 mmol/kg, DMSA reduced the kidney lead concentration 45%, while the monoesters caused reductions of 56-73%. DMSA lowered the brain lead concentration 35% on the 5-day treatment regimen, while the monoesters evoked reductions of 59-75%. Mi-ADMS was equally effective when given orally or i.p. The i.p. LD50 value of this analog in mice is 3.0 mmol/kg, a value which lies between the reported LD50 doses of DMSA (16.0 mmol/kg) and dimercaprol (1.1 mmol/kg). It is suggested that the ability of these monoesters to cross cell membranes may account for their superiority to DMSA in mobilizing brain lead in this animal model.
Walker
E M
EM
John L. McClellan Memorial Department of Veterans Affairs Medical Center, Little Rock, AR.
Stone
A
A
Milligan
L B
LB
Gale
G R
GR
Atkins
L M
LM
Smith
A B
AB
Jones
M M
MM
Singh
P K
PK
Basinger
M A
MA
D000818:Animals; D001921:Brain / Q000378:metabolism; D004952:Esters; D007668:Kidney / Q000378:metabolism; D007854:Lead / Q000493:pharmacokinetics*; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D004113:Succimer / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000633:toxicity
D004952:Esters; D007854:Lead; D004113:Succimer