Toshiya Honda

Comparative effects of three chelating agents on distribution and excretion of cadmium in rats

Sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC), which was newly synthesized, 2,3-dimercaptopropanol (BAL), and N-methyl-D-glucamine dithiocarbamate (NMG-DTC) were compared for their relative efficacies in the distribution and excretion of cadmium in rats exposed to cadmium. Rats were injected ip with 109CdCl2 (1 mg Cd and 10 microCi 109Cd/kg) and 3 days later, they were treated with the chelating agents (400 mumol/kg) every other day for 2 weeks. These chelating agents were effective in removing cadmium from the body without increasing the amount of cadmium in the kidney. After treatment with these chelating agents, cadmium was excreted mainly in the feces through the bile and the fecal excretion of cadmium by NBG-DTC was significantly larger than that by BAL or NMG-DTC. The hepatic cadmium content after treatment with NBG-DTC was much more decreased than that with BAL or NMG-DTC. The renal cadmium content was decreased only after treatment with NBG-DTC. These chelating agents did not result in the redistribution of cadmium to brain, testes, and heart. The growth of rats was little retarded by treatment with NBG-DTC and NMG-DTC, but was retarded by treatment with BAL. The treatment with NBG-DTC decreased the tissue amounts of Zn, Fe, and Mn to a small extent as compared with the treatment with cadmium alone. The results of this study reveal that the injection of NBG-DTC to rats pretreated with cadmium can more effectively remove cadmium from the body without the mobilization of cadmium to the kidney, the critical organ in cadmium toxicity, and without redistribution of cadmium to other tissues such as brain, testes, and heart, than injection of BAL and NMG-DTC.

Effect of N-benzyl-d-glucamine dithiocarbamate on distribution and excretion of cadmium in rats

The effect of sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC) on the distribution and excretion of cadmium in rats exposed to cadmium and the chemical form and intestinal reabsorption of cadmium compound excreted in the bile were studied. Rats were injected intraperitoneally with 109CdCl2 (1 mg Cd and 10 microCi 109Cd/kg) and 24 h later, they were injected with NBG-DTC (400 or 1200 mumol/kg). The biliary excretion of cadmium was remarkably increased by intraperitoneally injection of NBG-DTC, while there was only a small increase in urinary excretion of cadmium. Such an enhancement effect of NBG-DTC on the biliary excretion of cadmium was much larger at the high dose (1200 mumol/kg) of NBG-DTC. The treatment with NBG-DTC significantly decreased the cadmium content in the liver at the dose of 1200 mumol/kg and did not result in the undesirable redistribution of cadmium to the tissues, such as brain, testes, heart and lung. In addition, it was found that the cadmium compound excreted in the bile was mainly characterized as cadmium-NBG-DTC and which was not reabsorbed from the intestinal tracts.

Effect of N-benzyl-D-glucamine dithiocarbamate on the renal toxicity produced by subacute exposure to cadmium in rats.

The effect of N-benzyl-D-glucamine dithiocarbamate (BGD) on the renal toxicity produced by subacute exposure to cadmium in rats was studied. Rats were injected sc with CdCl2 (1.5 mg Cd/kg) daily for 26 days and thereafter they received 13 injections of BGD (400 mumol/kg) every other day. Urinary protein concentration and AST activity significantly increased after 20 days of cadmium treatment. The pattern of the increase in the urinary excretion of cadmium after cadmium treatment was consistent with that in the urinary excretion of protein and AST. Urinary excretion of amino acid increased gradually after the cessation of cadmium treatment. BGD treatment significantly decreased the urinary excretion of protein, aspartate aminotransferase (AST), and amino acid. Plasma AST activity was elevated 8 days after the beginning of cadmium treatment, indicating that the hepatic damage occurred prior to the renal damage. In addition, the microscopic examination of renal tissue from cadmium-treated rats revealed the necrosis of the proximal tubular cells. The cadmium concentrations in liver and kidney were significantly decreased by BGD treatment. The results of this study indicate that BGD treatment is effective in decreasing the cadmium concentrations in liver and kidney, resulting in the therapeutic effect on the cadmium-induced renal damage.

Effects of chelating agents on biliary and urinary excretion and tissue distribution of cadmium in rats

Sodium N-benzyl-D-glucamine dithiocarbamate (NBG-DTC), which was newly synthesized, sodium N-methyl-D-glucamine dithiocarbamate (NMG-DTC), and 2,3-dimercapto-1-propanol (BAL) were evaluated for their efficacy in mobilization of cadmium from the body using rats which had received cadmium, 30 min and 24 h earlier. At both 30 min and 24 h after treatment with cadmium, these chelating agents significantly enhanced the biliary excretion of cadmium, but did not influence the urinary excretion of the metal. Such an enhancement effect of NBG-DTC on the biliary excretion of cadmium was much larger than that of NMG-DTC or BAL. These chelating agents were effective in mobilizing cadmium from the liver at 30 min after pretreatment with cadmium. NBG-DTC showed the largest effectiveness on the depression of cadmium content in the liver. However, the contents of cadmium in the liver and kidney of rats given cadmium, 24 h earlier, did not significantly change at 3 h after treatment with the chelating agents. These results show that the injection of NBG-DTC at both 30 min and 24 h after treatment with cadmium can much more effectively mobilize cadmium from the body mainly through the bile without redistribution of cadmium to tissues than injection of NMG-DTC and BAL.

Urinary metabolites of 2,6-diisopropylnaphthalene in rats.

Metabolism of 2,6-diisopropylnaphthalene (2,6-DIPN) in rats was found to proceed exclusively through oxidation of the isopropyl chain of the molecule. Five unconjugated metabolites were isolated from the urine and identified: 2,6-naphthalenedi(2-propan)-2-ol, 2-[6-(1-hydroxy-1-methyl)ethylnaphthalen-2-yl]-2-propionic acid, 2,6-naphthalenedi-2-propionic acid, 2-[6-(1-hydroxy-1-methyl)ethylnaphthalen-2-yl]-2-hydroxypropionic acid, and 2-[6-(1-hydroxy-1-methyl)ethylnaphthalen-2-yl]-1,2-propanediol, together with a small amount of the unchanged compound. The identification of these metabolites was made by means of mass, infrared, and nuclear magnetic resonance spectrometry. The presence of glucuronides of five metabolites described above was also suggested by thin-layer and gas-liquid chromatography of the extract that was obtained after hydrolysis by beta-glucuronidase. In addition, the quantitative determination of metabolites indicated that these five were the major urinary metabolites of 2,6-DIPN, and that the total urinary excretion of these metabolites in 24 hr after administration was about 23% of the dose.

Effects of three proteins on absorption of cadmium in rats.

The effects of 3 proteins on the gastrointestinal absorption of cadmium were studied. Glycinin and ovalbumin significantly decreased cadmium in liver and the total cadmium in the tissues of rats following a single oral administration of cadmium. In addition, in rats fed continuously with the experimental diets containing cadmium together with proteins, glycinin and ovalbumin significantly decreased the contents of cadmium in the tissues. These results show that the proteins depressed the gastrointestinal absorption of cadmium. Moreover, the effects of cadmium on various digestive enzymes for proteins and the pepsin or pepsin-pancreatin digestion of the proteins were examined. As a result it is likely that the inhibitory effect of cadmium on the intestinal digestion of these proteins is one of the causes of the inhibitory effects of the proteins on the intestinal absorption of cadmium in rats. The undigested oligopeptides may decrease the amount of free cadmium available to be absorbed from the intestine by binding cadmium itself, resulting in decreased intestinal absorption of cadmium.

Comparison of effectiveness of 3 dithiocarbamates on excretion and distribution of cadmium in rats and mice

Sodium N-benzyl-D-glucamine dithiocarbamate (BGD), sodium N-p-methylbenzyl-D-glucamine dithiocarbamate (MBGD), and sodium N-p-isopropylbenzyl-D-glucamine dithiocarbamate (PBGD), which were recently synthesized, were evaluated for their efficacy in the distribution and excretion of cadmium in rats and mice exposed to cadmium. Rats and mice were injected i.p. with 109CdCl2 (1 mg Cd/kg and 2 microCi 109Cd/one animal) and 3 days later, they were treated with the dithiocarbamates (400 mumol/kg) every other day for 2 weeks. These dithiocarbamates were effective in removing cadmium from the body without increasing the cadmium content in the kidney. After treatment with BGD, MBGD, and PBGD, cadmium was excreted mainly in the feces and the effect of MBGD and PBGD on the fecal excretion of cadmium was much larger than that of BGD. The treatment with these dithiocarbamates did not cause the redistribution of cadmium to brain, testes, and heart in rats and mice. The treatment of mice with PBGD decreased the concentrations of essential metals in liver, kidney, and brain. The extent of acute toxicity of the dithiocarbamates in mice was in the order PBGD greater than MBGD greater than BGD.

Identification and determination of urinary metabolites of 2-isopropylnaphthalene in rabbits

SummaryFour unconjugated metabolites, which were produced through the oxidation of the isopropyl chain of 2-isopropylnaphthalene (2-IPN), were isolated from the urine of rabbits receiving 2-IPN orally and identified: 2-(2-naphthyl)propionic acid, 2-(2-naphthyl)-2-propanol, 2-(2-naphthyl)-1,2-propanediol, and 2-(2-naphthyl)-2-hydroxypropionic acid, together with a small amount of the unchanged compound. Further, the unconjugated metabolites, which were produced through the oxidation of the naphthalene ring, were isolated and identified: 2-isopropylnaphthols and 2-isopropyl-5,6 (or 7,8)-dihydronaphthalene-5,6 (or 7,8)-diol. The identification of these metabolites was made by means of TLC, GLC, MS, IR, GC/MS, and FT-NMR. The presence of glucuronides of metabolites B, C, D, F, and H was also suggested by TLC and GLC of the extract obtained after hydrolysis by β-glucuronidase. In addition, quantitative determination of the metabolites indicated that the total urinary excretion of the metabolites except 2-isopropylnaphthols in 24 hr after administration was about 29% of the dose.

Protective effects of dextran sulfate and polyvinyl sulfate against acute toxicity of paraquat in mice

The protective effects of sodium dextran sulfate (SDS) and potassium polyvinyl sulfate (PPS) against the acute toxicity of paraquat (PQ) in mice were studied. The survival rates of mice treated with SDS (2000 mg/kg) or PPS (2000 mg/kg) immediately after PQ ingestion (200 mg/kg) were 100% or 100%, respectively. When treated with SDS (2000 mg/kg) or PPS (2000 mg/kg) 15 or 30 min after PQ ingestion (200 mg/kg), the survival rates were 83% or 67% for SDS-treated groups and 67% or 33% for PPS-treated groups, respectively. Treatment with SDS (2000 mg/kg) or PPS (2000 mg/kg) immediately after oral administration of PQ (200 mg/kg) increased the fecal excretion of PQ, decreased the urinary excretion of PQ and decreased the contents of PQ in the lung, liver and kidney. Such effects of SDS and PPS were reduced in the treatment with these drugs at 15 min after PQ. The in situ small intestinal absorption of PQ was significantly reduced in the presence of SDS or PPS. The binding of PQ to SDS or PPS was determined by an ultrafiltration method. These results indicate that SDS and PPS inhibit the gastrointestinal absorption of PQ on the basis of the increased intestinal transit of PQ and the binding of PQ to the drugs resulting in the protective effectiveness of SDS and PPS on the acute toxicity of PQ.

Effect of 2-Isopropylnaphthalene on Pulmonary Phospholipid in Rats

The intraperitoneal administration of 2-isopropylnaphthalene (2-IPN) (3000 mg/kg) to rats resulted in an increase of phospholipids and phosphatidylcholine in the pulmonary lavage fluid. The fatty acid composition of the phosphatidylcholine in the fluid of rats so treated, however, was unchanged from that of untreated animals. Prior treatment of rats with piperonyl butoxide, a known cytochrome P-450 inhibitor, resulted in an inhibition of the above increase of phospholipids and phosphatidylcholine. In contrast, prior treatment with diethyl maleate, which induced depletion of reduced glutathione (GSH) in the tissue, enhanced the effect of 2-IPN on phospholipid and phosphatidylcholine contents in the pulmonary lavage fluid. To confirm the possible participation of GSH, pulmonary nonprotein-SH (NP-SH) was determined. Treatment with 2-IPN resulted in a decrease of NP-SH, and the administration of 2-IPN to rats pretreated with diethyl maleate caused a significant decrease of NP-SH compared to 2-IPN given without pretreatment. From these results, it is suggested that reactive metabolites such as 2-IPN-epoxides are produced, leading to an increase in secretion of pulmonary surfactant from alveolar Type II cells.