Conrad C C, Walter C A, Richardson A, Hanes M A, Grabowski D T
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio 78284-7762, USA.
J Toxicol Environ Health. 1997 Dec 26;52(6):527-43. doi: 10.1080/00984109708984079.
To date, numerous correlative studies have implicated metallothionein in the detoxification of heavy metals and in the regulation of metal distribution within an organism. In the present study cadmium-binding proteins (metallothionein equivalents), cadmium acute toxicity, and cadmium distribution in tissues and subcellular fractions were compared in metallothionein-I and -II deficient (MT-/-) mice and the parental strain carrying intact metallothionein genes (MT+/+) to determine if the absence of metallothionein altered any of these parameters. In an uninduced state, MT-/- mice expressed lower levels of cadmium-binding proteins relative to MT+/+ mice in several tissues. Administration of zinc enhanced the levels of cadmium-binding proteins in liver, small intestine, kidney, pancreas, and male sex organs, but not in cecum or brain of MT+/+ mice compared to zinc pretreated MT-/- mice. The cadmium LD50 was similar for MT-/-, MT+/+, and zinc-pretreated MT-/- mice (15-17 mumol CdCl2/kg body weight delivered i.p.). However, zinc-pretreated MT+/+ mice had a cadmium LD50 of 58-63 mumol CdCl2/kg body weight. Over two-thirds of cadmium was found in liver, cecum, small intestine, and kidney in both MT+/+ and MT-/- mice; therefore, metallothionein levels do not appear to play a major role in the tissue distribution of cadmium. However, after zinc pretreatment, MT+/+ mice accumulated more cadmium in the liver and less in other tissues, whereas the amount of cadmium in the liver was not altered by zinc pretreatment in MT-/- mice. In general, the cytosolic/particulate ratio of cadmium was significantly higher in tissues of noninduced MT+/+ mice relative to MT-/- mice. This difference was accentuated after zinc pretreatment. Together these results indicate that basal levels of metallothionein do not protect from the acute toxicity of a single i.p. cadmium challenge. Furthermore, it does not appear that the cytosolic compartmentalization of cadmium is correlated with reduced toxicity.
迄今为止，众多相关性研究表明金属硫蛋白参与重金属解毒以及生物体中金属分布的调节。在本研究中，对金属硫蛋白-I和-II缺陷型（MT-/-）小鼠以及携带完整金属硫蛋白基因的亲代品系（MT+/+）小鼠的镉结合蛋白（金属硫蛋白当量）、镉急性毒性以及镉在组织和亚细胞组分中的分布进行了比较，以确定金属硫蛋白的缺失是否会改变这些参数中的任何一个。在未诱导状态下，相对于MT+/+小鼠，MT-/-小鼠在多个组织中表达的镉结合蛋白水平较低。与锌预处理的MT-/-小鼠相比，给予锌可提高MT+/+小鼠肝脏、小肠、肾脏、胰腺和雄性生殖器官中镉结合蛋白的水平，但在盲肠或大脑中则不然。MT-/-小鼠、MT+/+小鼠以及锌预处理的MT-/-小鼠的镉半数致死剂量（LD50）相似（腹腔注射15 - 17 μmol CdCl2/kg体重）。然而，锌预处理的MT+/+小鼠的镉LD50为58 - 63 μmol CdCl2/kg体重。在MT+/+和MT-/-小鼠中，超过三分之二的镉存在于肝脏、盲肠、小肠和肾脏中；因此，金属硫蛋白水平似乎在镉的组织分布中不起主要作用。然而，锌预处理后，MT+/+小鼠在肝脏中积累的镉更多，而在其他组织中积累的镉更少，而锌预处理并未改变MT-/-小鼠肝脏中的镉含量。总体而言，未诱导的MT+/+小鼠组织中镉的胞质/颗粒比例相对于MT-/-小鼠显著更高。锌预处理后这种差异更加明显。这些结果共同表明，金属硫蛋白的基础水平并不能保护机体免受单次腹腔注射镉所致的急性毒性。此外，镉的胞质区室化似乎与毒性降低无关。
