Differences in the toxicities observed for dithiocarbamates have been proposed to result from the influence of nitrogen substitution, oxidation state, and route of exposure. To better characterize the fate of dithiocarbmates in vivoas a function of structure and route of exposure, rats were administered equimolar doses of carbon disulfide (CS2), N-methyldithiocarbamate, pyrrolidine dithiocarbamate, N,N-diethyldithiocarbamate, or disulfiram daily for five days, either po or ip, and sequential blood samples obtained. Protein dithiocarbamates formed by the in vivo release of CS2, parent dithiocarbamate, and protein-bound mixed disulfides were assessed in plasma and hemolysate by measuring toluene trithiocarbonate generated upon treatment with toluene-3, 4-dithiol (TdT). To aid in determining the bioavailability of CS2 from the administered dithiocarbamates, the urinary CS2 metabolites, 2-thiothiazolidine-4-carboxylic acid (TTCA) and 2-thiothiazolidin-4-ylcarbonylglycine (TTCG), were also determined. The levels of TdT-reactive moieties detected depended upon both the compound administered and the route of exposure. Parent dithiocarbamates, with the exception of disulfiram, were eliminated from blood within 24 h; but protein associated TdT-reactive moieties persisted and accumulated with repeated exposure, regardless of the route of exposure. N-Methyldithiocarbamate demonstrated the greatest potential to produce intracellular globin modifications, presumably through its unique ability to generate a methylisothiocyanate metabolite. Urinary excretion of TTCA and TTCG was more sensitive than TdT analysis for detecting dithiocarbamate exposure, but TdT analysis appeared to be a better indicator of in vivo release of CS2 by dithiocarbamates than were urinary CS2 metabolites. These data suggest that CS2 is a more important metabolite, following oral exposure, than are other routes of exposure, e.g., inhalation or dermal. In addition, data also suggest that acid stability, nitrogen substitution, and route of exposure are important factors governing the toxicity observed for a particular dithiocarbamate. 相似文献
Proliferative vitreoretinopathy (PVR) is oneof the most common eye diseases that couldlead tosevere vision i mpairment and tend to cause blind-ness .It has beenfound that the abnormal prolifer-ation of retinal pigment epithelium(RPE) plays akey role in the onset and development of PVR.Under pathologic status ,such as rhegmatogenousdetachment of retina and severe ocular trauma ,RPE cells may migrate and proliferate because ofthe sti mulations of cytokines or chemokines ,thusmay lead to path… 相似文献
A fused aromatic furan‐substituted diketopyrrolopyrrole and novel diphenylfumaronitrile conjugated building blocks are used for the synthesis of an alternating copolymer ( DPFN‐DPPF ) via Suzuki polycondensation. In this paper, the first attempt to use the diphenylfumaronitrile building block for the synthesis of conjugated polymer is described. The number‐average and weight‐average molecular weights calculated for DPFN‐DPPF are 20 661 and 66 346 g mol?1, respectively. The optical bandgap calculated for DPFN‐DPPF is 1.53 eV whereas the highest occupied molecular orbital (HOMO) value calculated by photoelectron spectroscopy in air (PESA) is 5.50 eV. The calculated HOMO value is lower, which is suitable for stable organic electronic devices. DPFN‐DPPF polymer is used as an active layer in bottom‐contact bottom‐gate organic thin‐film transistor devices and the thin film exhibits a hole mobility of 0.20 cm2 V?1 s?1 in air.
This investigation aimed to modify finasteride ( 1 ) to finasteride dithiocarbamate ( 2 ) for subsequent synthesis of the rhenium analogue ( 3 ) and [99mTc]tricarbonyl complexes ( 4 ), to assess its prostate cancer (PCa) targeting potential in a rat model. To validate the identity of ( 4) , reference ( 3) has been synthesized by using fac‐[Net4]2[ReBr3(CO)3] precursor and characterized by 1H‐NMR, 13C‐NMR, ESI‐MS, and elemental analysis. The analogue ( 4) was synthesized by using fac‐[99mTc(H2O)3(CO)3]+ precursor, and its structure was confirmed by comparative HPLC by using ( 3) as a reference. Further, the suitability of ( 4) as a PCa imaging agent was investigated in vitro and in vivo. At room temperature, ( 4) had ≥99% radiochemical purity and remained ≥84% stable in serum. In preclinical studies, biodistribution of ( 4) in histopathologically established rat model showed adequately high in vivo uptake in the prostate attracting the possibility of using it for noninvasive imaging of PCa. 相似文献
Aim: To investigate the effects of a novel dithiocarbamate derivative TM208 on human breast cancer cells as well as the pharmacoki- netic characteristics of TM208 in human breast cancer xenograft mice. Methods: Human breast cancer MCF-7 and MDA-MB-231 cells were treated with TM208 or a positive control drug tamoxifen. Cell pro- liferation was examined using SRB and colony formation assays. Cell apoptosis was analyzed with Annexin V-FITC/PI staining assay. Protein expression was examined with Western blot, ELISA and immunohistochemical analyses. MCF-7 breast cancer xenograft nude mice were orally administered TM208 (50 or 150 mg.k$1〈1-1) or tamoxifen (50 mg.kgl〈t-~) for 18 d. On d 19, the tumors were collected for analyses. Blood samples were collected from the mice treated with the high dose of TM208, and plasma concentrations of TM208 were measured using LC-MS/MS. Results: Treatment of MCF-7 and MDA-MB-231 cells with TM208 dose-dependently inhibited the cell proliferation and colony formation in vitro (the IC~o values were 36.38+3.77 and 18.13+0.76 pmol/L, respectively). TM208 (20-150pmol/L) dose-dependently induced apoptosis of both the breast cancer cells in vitro. In MCF-7 breast cancer xenograft nude mice, TM208 administration dose-depend- ently reduced the tumor growth, but did not result in the accumulation of TM208 or weight loss. TM208 dose-dependently inhibited the phosphorylation of EGFR and ERK1/2 in both the breast cancer cells in vitro as well as in the MCF-7 xenograft tumor. Conclusion: Inhibition of EGFR autophosphorylation plays an important role in the anticancer effect of TM208 against human breast cancer. 相似文献
目的:探讨核因子KB(NF-κB)抑制剂吡咯烷二硫代氨基甲酸盐(PDTC)对大鼠急性坏死性胰腺炎(ANP)的预防治疗作用。方法:大鼠80只随机分为正常对照组(Z)、胰腺炎组(Y)和干预纽.干预组又分为建模前1h PDTC干预组(A)、建模后1h PDTC干预组(B)和建模后6h干预组(C).干预组按不同时间ip PDTC.建模后6,12,24 h分批处死,临床全自动生化仪检测血清谷丙转氨酶(ALT)和淀粉酶(AMY),用凝胶迁移率改变分析法(EMSA)测定胰腺和肝脏中NF-κB的活性.同时观察胰腺和肝脏的病理改变.结果:正常大鼠组织中几乎测不到NF-κB的活性,与Z组比较,Y组胰腺和肝脏组织中6,12,24 h NF-κB活性分别明显增加(P<0.001).建模前1h,1h后使用PDTC,胰腺和肝脏组织中NF-κB活性均受到抑制(18.14±3.30,23.79±3.62 vs 24.82±4.57:10.68±2.51,13.83±2.70 vs 16.38±2.50;P<0.05),Y组血清ALT,AMY均高于对照组.病理学检查可以见到Y组和A,B,C组的胰腺和肝脏均有炎性改变,但A组较Y组明显为轻.结论:NF-κB的异常活化与SAP以及肝损伤有明显关系:PDTC对SAP时肝损伤的发生有一定的预防作用. 相似文献