Efficacy of amphipathic dithiocarbamates in intracellular cadmium mobilization and in modulation of hepatic and renal metallothionein in cadmium pre-exposed rat.
Forty-eight hours after an intraperitoneal injection of cadmium chloride (1.5 mg Cd/kg) to female albino rats, Cd was mainly localized in the hepatic and renal supernatant cytosolic fraction (SCF). Seventy-two hours later, the total hepatic burden remained unchanged but the total renal burden was enhanced, showing its tendency to accumulate in the kidney. A single dose (0.4 mmol/kg, i.p.) of sodium N-benzyl-D-glucamine dithiocarbamate (BG.DTC) or sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeO.BG.DTC), 24 h after Cd injection, efficiently mobilized Cd from hepatic SCF, apparently from cadmium-metallothionein (Cd-MT); MeO.BG.DTC also removed Cd from hepatic nuclear mitochondrial fraction. This treatment, however, increased the renal burden of Cd, indicating that the chelating agents, at least partly, transport Cd from the liver and possibly from other sites into the kidney. Three doses of the chelators further enhanced mobilization of Cd from hepatic as well as renal SCF, as corroborated by its enhanced urinary and, to a greater extent, fecal excretion. Hepatic and renal MT were induced several-fold above normal after a single dose of Cd as well as single or repeated doses of BG.DTC or MeO.BG.DTC. Seventy-two hours after a Cd injection, the hepatic MT declined to half of the induced level while the renal MT remained elevated. Administration of BG.DTC or MeO.BG.DTC in Cd pre-treated rats produced an additive response in hepatic MT, but the response in renal MT was less than additive at one dose and slightly declined after three doses. Hepatic Zn and Cu and renal Zn increased on treatment with Cd but were depleted after a single or repeated injection of BG.DTC or MeO.BG.DTC in normal as well as in Cd pre-exposed animals. The results indicate that intracellular access of amphipathic dithiocarbamates effectively mobilizes MT-bound Cd, which is preferentially excreted in the feces, and helps avoid further burden on the kidney and consequent nephrotoxicity. Additionally, MeO.BG.DTC was a better inducer of hepatic MT to help increased capture of toxic metal from the initial circulation and consequent toxicity.
Tandon
S K
SK
Chelation Therapy Section, Industrial Toxicology Research Centre, Lucknow, India.
Prasad
S
S
Singh
S
S
Agarwal
D K
DK
D000818:Animals; D002104:Cadmium / Q000378:metabolism*; D019256:Cadmium Chloride / Q000633:toxicity*; D002614:Chelating Agents / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003300:Copper / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005260:Female; D006706:Homeostasis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008668:Metallothionein / Q000378:metabolism*; D000442:Octanols; D051381:Rats; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000494:pharmacology; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism
D002614:Chelating Agents; D000442:Octanols; D013859:Thiocarbamates; D002104:Cadmium; C060427:N-(4-methoxybenzyl)glucamine dithiocarbamate; D013012:Sorbitol; D003300:Copper; D008668:Metallothionein; D015032:Zinc; D019256:Cadmium Chloride; C048763:N-benzylglucamine dithiocarbamate