Defense of mammalian body against heavy metal-induced toxicities: Sequestration by the choroid plexus and elimination via the bile.
AdvisorAposhian, H. Vasken
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PublisherThe University of Arizona.
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AbstractTissue sequestration and biliary elimination are two of the important mechanisms by which mammalian body defends against heavy metal insults. In rats or rabbits that had received Pb, Cd, Hg, As and ²¹⁰Po, these metal ions were sequestered in the choroid plexus at concentrations of Pb, Cd, Hg, As and Po that were 57, 33, 12, 13 and 5 times higher, respectively, than those found in the brain cortex. In addition, the concentrations of these heavy metal ions were many fold greater in the choroid plexus than in the CSF or blood. The accumulation of Pb in the choroid plexus was dose-dependent and time-related. When the choroid plexus was incubated, in vitro, with ouabain, the latter significantly inhibited the uptake of Cd from the CSF side of the choroid plexus. Cystine concentration was four times greater in the choroid plexus than in brain cortex. Results suggest that the choroid plexus sequesters toxic metal and metalloid ions. It appears to do this in order to protect the CSF and brain from toxic heavy metals in the blood. The effect of N-(2,3-dimercaptopropyl) phthalamidic acid (DMPA), meso-dimercaptosuccinic acid (DMSA) and 2,3-dimercapto-1-propane sulfonic acid (DMPS) on biliary excretion of Cd was studied in rat chronic intoxication mode. DMPA (0.10 mmol/kg, iv), when given to rats three days after exposure to Cd, elicited within 30 min a 20-fold increase in biliary Cd excretion. GSH in rat bile was also increased three fold as compared to control. Neither DMSA nor DMPS increased biliary Cd or GSH. Upon iv administration, DMPA, not DMSA, appeared in bile. An altered, presumably disulfide, form of DMPS was also found in bile. Incubation of DMPA or DMSA with Cd-saturated MT resulted in the removal of Cd from MT. DMPS, however, promoted the formation of MT polymers. DMPA protected biliary GSH from autoxidation. Gel filtration and autoradiographic study of rat bile samples showed that the radioactivity of Cd was correlated with both GSH and DMPA. The evidence supports the mechanism that the increase of biliary Cd by DMPA is the result of DMPA entering cells and removing Cd from MT. Protection of GSH autoxidation by DMPA may facilitate Cd elimination via the bile.
Degree ProgramPharmacology and Toxicology