| Cadmium and its compounds, which are highly toxic to human body, have been widely applied in industry. Cadmium (Cd) can enter the body through occupational exposure or food chain, which resulted from industrial discharge and bioaccumulation. Cadmium is not only a kind of unnecessary element to human being, but also a mightily accumulative material, with a half-life of about 30 years. With the strong acute and chronic toxicity, cadmium can cause damages in kidney, liver, lung, bone, cardiovascular system and reproductive system. Determined are also their immunity suppression, carcinogenicity, teratogenicity and mutagenesis. Cadmium is listed as the 6th toxic substance to endanger the human body by Agency for Toxic Substances and Disease Registry (ATSDR) of USA.For the time being, there are still not effective drugs or treatment methods for the cadmium poisoning patients but only some supporting treatments. Regular metal chelating agents can not be used because when cadmium is reabsorbed in the renal tubule, it damages the kidney to a much higher degree. It is urgently needed that a safe and effective drug can be produced for the cadmium poisoning patients.Objective To Explore the effects of a new chelating agent G-Met-DTC(D-3) on the excretion of accumulated cadmium in exposed mice.Methods 1. Experiment of acute cadmium intoxicated model in miceMale NIH mice were given Cd-ME mixture (dose:75,23.73,7.5,2.37, 0.75μmol/kg CdCl2 and 1500,474.68,150,47.47,15μmol/kg ME), ip for once. Animals were executed 14 days after the injection. Indexes of kidney cadmium, blood cadmium and pathological changes of kidney, liver and testicles were considered to ascertain the best dosage of acute cadmium intoxication model in mice.2. Cd-induced chronic renal damage model in ratsAccordancing to the orthogonal design L8(34), male SD rats were given Cd-ME mixture (dose:3.0,6.0,12.0μmol Cd/kg and 60.0,120.0,240.0μmol ME/kg), ip for 1-5 days. Animals were then executed on the 7th,21st and 35th day. Indexes of kidney cadmium, blood cadmium, Uβ2-MG and pathological changes of kidney were analyzed to selecte the best method for Cd-induced chronic renal damage model in rats.3. Effect of the intermediate of chelating agent on renal excretion of cadmiumCadmium intoxicated mice were treated with D-2 and B-2, the intermediates of chelating agent, to observe the effect of excretion of accumulated Cd in kidney, liver and brain, and on the distribution of trace elements in kidney, liver and brain in the exposed mice. The result was applied as the guidance to promote a new drug for cadmium elimination.4. Effect of chelating agent on renal excretion of cadmiumCadmium intoxicated mice were treated with D-3 and B-3, two kinds of chelating agents, as well as EDTA, to ascertain the effect of excretion of accumulated Cd in kidney, liver and brain, and the distribution of trace elements in kidney, liver and brain in exposed mice.Result 1. Experiment of acute cadmium intoxicated model in miceCompared to the control group, cadmium in blood and kidney were high in all model groups. All animals in group 1 (75μmol/kg CdCl2+1500μmol/kg ME) died 1 day after the treatment. Anmials in group 2 and 3 (23.73μmol/kg CdCl2+ 474.68μmol/kg ME and 7.5μmol/kg CdCl2+150μmol/kg ME) were observed to have obvious damages in kidney and testicle. No obvious abnormalities were observed in animals of Group 4 and 5 (2.37μmol/kg CdCl2+47.47μmol/kg ME and 0.75μmol/kg CdCl2+15μmol/kg ME).2. Cd-induced chronic renal damage model on ratCompared to the control group, U02-MG in group3 (3μmol Cd/kg+60μmol ME/kg, ip 5d, executed on day 35) and group 8 (2μmol Cd/kg+240μmol ME/kg, ip. 3d, executed on day 35) were increased respectively on day 28 and day 35. Cadmium in kidney of group 6 (6μmol Cd/kg+120μmol ME/kg,ip.5d, executed on day 21), group 8(2μmol Cd/kg+240μmol ME/kg, ip.3d, executed on day 35) and group 9(12μmol Cd/kg+240μmol ME/kg,ip.5d, executed on day 7) were increased (9.930±6.482,16.179±2.256,29.003±7.050μg/g wet weight). Blood cadmium in group 6 and group 9 were increased, reaching to 1.319±0.458 and 1.254±0.089μg/L. Pathological results revealed that tubulus renalis vacuole was found in group 6, group 8 and group 9. 3. Effect of midbody chelating agent on renal excretion of cadmiumD-2 and B-2 could significantely reduce the cadmium levels in the brain of mice. The former one could also reduce Cd in kidney, but expressed no obvious effect on kidney Cd and liver Cd. D-2 could reduce brain zinc (Zn) and kidney calcium (Ca), lowering calcium to the level of the controlled, while testicle/body ratio were increased (P<0.05). Compared with the Cd control group, the contents of trace elements remained unchanged in D-2 group.4. Effect of chelating agent on renal excretion of cadmiumAll mice were survived in the course of D-3 treatment. D-3 could significantly reduce Cd in brain, kidney and liver, and counteract the increases of liver Zn, kidney Zn and liver Cu caused by cadmium exposure. No obvious pathology changes could be found on the highest dose of D-3 group (1.Ommol/kg). On the other hand,60% of the animals died after the treatment of EDTA. EDTA not only could significanty reduce Cd in kidney and liver, but also reduce the content of Ca in kidney which was obviously lower than that of the normal level. Pathological examination in EDTA group revealed disarrangement of seminiferous tubule and interstitial tissue dropsy. When animals were treated with B-3, they screamed and struggled. Although B-3 would be irritative, all animals survived in the course of treatment. Compared with the Cd control group, B-3 group could reduce Cd in kidney, but remained the trace elements unchanged.ConclusionRelatively ideal animal model of acute cadmium intoxication in mice can be duplicated with 2.37μmol/kg CdC12+47.47μmol/kg ME, ip, which increased the cadmium burden in blood and kidney but without obvious damage to the organs of the mice. A sub-chronic Cd-induced renal damage model can be duplicated with 3.0μmol Cd/kg+60.0μmol MT/kg,ip for 5 days, which elicits renal malfunction but without pathological changes in the organs. Treated with D-2 and the B-2, two kinds of intermediates of chelating agent, Cd of the exposed mice decreases obviously. It is concluded that the effect of D-2 is better than that of B-2, for D-2 can reduce the content of Cd in kidney from 52.67μg/g to reduce to 41.62μg/g (21%), while B-2 can only reduce the content of Cd in kidney to 48.44μg/g(8.0%). D-3, a drug further synthesized from D-2, has a good effect on cadmium reduction in kidney, liver and brain. D-3 has a strong selectivity to cadmium, providing the protective function to the kidney. D-3 can reduce the content of Cd in kidney by 48%, minimize the hepatic toxicity and testicle toxicity of cadmium, but without obvious adverse effect on trace elements. A very good prospect is expected for that D-3 can not only eliminate Cd from kidney and liver, but also lessen the transfer of Cd to the brain. |
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