title: Decorporation of Pu/Am Actinides by Chelation Therapy: New Arguments in Favor of an Intracellular Component of DTPA Action.
abstract: Diethylenetriaminepentaacetic acid (DTPA) is currently still the only known chelating drug that can be used for decorporation of internalized plutonium (Pu) and americium (Am). It is generally assumed that chelation occurs only in biological fluids, thus preventing Pu/Am deposition in target tissues. We postulate that actinide chelation may also occur inside cells by a mechanism called "intracellular chelation". To test this hypothesis, rats were given DTPA either prior to (termed "prophylactic" treatment) or belatedly after (termed "delayed" treatment) Pu/Am injection. DTPA decorporation efficacy was systematically tested for both plutonium and americium. Both prophylactic and delayed DTPA elicited marked decreases in liver Pu/Am. These results can be explained by chelation within subcellular compartments where DTPA efficacy increased as a function of a favorable intracellular DTPA-to-actinide molar ratio. The efficacy of intracellular chelation of liver actinides decreased with the delay of treatment. This is probably explained by progressive actinide binding to the high-affinity ligand ferritin followed by migration to lysosomes. Intracellular chelation was reduced as the gap between prophylactic treatment and contamination increased. This may be explained by the reduction of the intracellular DTPA pool, which declined exponentially with time. Skeletal Pu/Am was also reduced by prophylactic and delayed DTPA treatments. This decorporation of bone actinides may mainly result from extracellular chelation on bone surfaces. This work provides converging evidence for the involvement of an intracellular component of DTPA action in the decorporation process. These results may help to improve the interpretation of biological data from DTPA-treated contamination cases and could be useful to model DTPA therapy regimens.
authors.affiliation: CEA/DSV/IRCM/Laboratoire de RadioToxicologie, Bruyères-le-Châtel, 91297 Arpajon cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Grémy
authors.affiliation: CEA/DSV/IRCM/Laboratoire de RadioToxicologie, Bruyères-le-Châtel, 91297 Arpajon cedex, France.
authors.forename: David
authors.initials: D
authors.lastname: Laurent
authors.affiliation: CEA/DSV/IRCM/Laboratoire de RadioToxicologie, Bruyères-le-Châtel, 91297 Arpajon cedex, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Coudert
authors.affiliation: CEA/DSV/IRCM/Laboratoire de RadioToxicologie, Bruyères-le-Châtel, 91297 Arpajon cedex, France.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Griffiths
authors.affiliation: CEA/DSV/IRCM/Laboratoire de RadioToxicologie, Bruyères-le-Châtel, 91297 Arpajon cedex, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Miccoli
mesh_terms: D000576:Americium / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D042541:Intracellular Space / Q000187:drug effects* / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D004369:Pentetic Acid / Q000378:metabolism* / Q000494:pharmacology; D011005:Plutonium / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D002614:Chelating Agents; D011005:Plutonium; D004369:Pentetic Acid; D000576:Americium