Involvement of active transport systems in the mobilization of cadmium by dithiocarbamates in vivo.
Previously, we reported that the action of cadmium (Cd) complexing dithiocarbamates, such as N-benzyl-D-glucamine dithiocarbamate (BGD) and N-p-hydroxymethylbenzyl-D-glucamine dithiocarbamate (HBGD), in removing Cd from the kidney involves a probenecid-sensitive organic anion transport system. However, other mechanisms responsible for Cd mobilizing effects of BGD and HBGD are still unclear. Therefore, in the present study we examined the effects of phloretin (an inhibitor of plasma membrane glucose carrier), phloridzin (an inhibitor of Na(+)-dependent active hexose transport) and alpha-aminoisobutyric acid (AIB, an inhibitor of amino acid transport) on the excretion and distribution of the chelating agents and Cd in mice. Phloretin pretreatment markedly decreased the biliary and urinary excretions of BGD and HBGD. Phloridzin pretreatment also decreased the biliary and urinary excretions of HBGD, but had no effect on the BGD. AIB pretreatment had no effect on the excretions of either BGD or HBGD. Phloretin pretreatment increased the hepatic and renal contents of BGD and HBGD. Contrary to this, phloridzin pretreatment decreased the hepatic content of BGD and hepatic and renal contents of HBGD, while AIB pretreatment decreased the renal contents of BGD and HBGD. The mobilizing effects of BGD and HBGD on the hepatic and renal Cd was also investigated using Cd-exposed mice. Phloretin or phloridzin pretreatment decreased the mobilizing effect of BGD and HBGD on the hepatic Cd, but had no effect on the renal Cd. These results suggest that BGD and HBGD are taken up into the liver and kidney by phloridzin- and phloretin-sensitive transport system, respectively; that Cd-BGD and Cd-HBGD complexes formed in the hepatic cells are secreted to the bile by phloridzin- and phloretin-sensitive transport systems; and that free BGD and HBGD secreted from these organ to the bile and urine might have occurred, at least in part, by different mechanisms.
Kamenosono
Takeshi
T
Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, 862-0973, Kumamoto, Japan.
Shimada
Hideaki
H
Funakoshi
Takayuki
T
Kojima
Shoji
S
D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors; D000621:Aminoisobutyric Acids / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002104:Cadmium / Q000493:pharmacokinetics* / Q000652:urine; D002614:Chelating Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors; D010693:Phloretin / Q000494:pharmacology; D010695:Phlorhizin / Q000494:pharmacology; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D013859:Thiocarbamates / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000652:urine; D014018:Tissue Distribution
D026905:Amino Acid Transport Systems; D000621:Aminoisobutyric Acids; D002614:Chelating Agents; D009004:Monosaccharide Transport Proteins; D013859:Thiocarbamates; D002104:Cadmium; C068198:N-4-hydroxymethylbenzylglucamine dithiocarbamate; D013012:Sorbitol; D010695:Phlorhizin; C048763:N-benzylglucamine dithiocarbamate; D010693:Phloretin