Mechanism of mobilization of renal and hepatic cadmium by dithiocarbamates in mice.
To clarify the mechanism of mobilization of renal and hepatic cadmium (Cd) by N-benzyl-D-glucamine dithiocarbamate (BGD) and N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD) in mice exposed to Cd, the effects of pretreatment with probenecid, an organic anion transport inhibitor, or with acivicin, a gamma-glutamyltranspeptidase (gamma-GTP) inhibitor and ureter-ligation were investigated on the excretion and distribution of chelating agents and Cd. The renal contents of BGD and HBGD were increased by ureter-ligation and decreased by acivicin pretreatment. The mobilizing effect of BGD on the renal Cd was inhibited by probenecid pretreatment. The action of HBGD in removing Cd from the kidney was inhibited by both probenecid pretreatment and ureter-ligation. These results suggest that BGD and HBGD are mainly taken up into the renal tubular cells through the basolateral membrane which is dependent on the action of gamma-GTP; that the Cd-BGD complex formed in the tubular cells is secreted by a probenecid-sensitive organic anion transport system through the basolateral membrane; and that the Cd-HBGD complex formed in the tubular cells is secreted to the tubular lumen by an organic anion transport system through the brush border membrane. Probenecid pretreatment increased the hepatic contents of BGD and HBGD and also promoted the effects of these chelating agents in removing Cd from the liver, indicating an inhibitory effect of probenecid on the glucuronidation of BGD and the secretion of HBGD from the kidney. These results suggest that BGD and HBGD are taken up into the liver and secreted from the organ to the bile by a transport system other than a probenecid-sensitive transport mechanism.
Kojima
S
S
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, Japan.
Kamenosono
T
T
Shimada
H
H
Funakoshi
T
T
D000818:Animals; D001646:Bile / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002104:Cadmium / Q000493:pharmacokinetics* / Q000633:toxicity; D002614:Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D007555:Isoxazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D011339:Probenecid / Q000494:pharmacology; D013012:Sorbitol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology*; D014513:Ureter / Q000601:surgery; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D002614:Chelating Agents; D007555:Isoxazoles; D013859:Thiocarbamates; D002104:Cadmium; C068198:N-4-hydroxymethylbenzylglucamine dithiocarbamate; D013012:Sorbitol; D005723:gamma-Glutamyltransferase; C048763:N-benzylglucamine dithiocarbamate; C006303:acivicin; D011339:Probenecid