Liu J, Kershaw W C, Liu Y P, Klaassen C D
Department of Pharmacology, University of Kansas Medical Center, Kansas City 66160.
Toxicology. 1992 Oct;75(1):51-62. doi: 10.1016/0300-483x(92)90125-x.
Susceptibility to cadmium (Cd) hepatotoxicity differs among inbred strains of mice. For example, C3H/HeJ mice are sensitive to Cd-induced hepatotoxicity, whereas DBA/2J mice are resistant. The mechanism of genetic predisposition to Cd hepatotoxicity is unknown. A contemporary theory for acute target organ intoxication maintains that Cd initially damages vascular endothelium and parenchymal cell injury is a secondary event that results from localized ischemia. In the present study, the hypothesis that hepatic endothelial cells (EC) of C3H mice are more susceptible to Cd toxicity than those of DBA mice was tested. Hepatic parenchymal and endothelial cells were grown separately on monolayer cultures for 22 h and subsequently treated with various concentrations of Cd. Hepatocellular toxicity was assessed by lactate dehydrogenase leakage and intracellular K+ loss, whereas endothelial cell injury was assessed by trypan blue exclusion and the inhibition of protein synthesis. The susceptibility of hepatocytes to the cytotoxic effects of Cd was identical between strains. In contrast, the vulnerability of EC to Cd intoxication was strain-dependent. When exposed to 2.5-10.0 microM Cd, EC of Cd-sensitive mice were more susceptible to the cytotoxic effects of Cd than those of Cd-resistant mice. Basal metallothionein (MT) levels as well as Cd uptake into EC were similar in the two strains. Following Cd exposure, EC of Cd-sensitive mice accumulated similar amounts of MT as EC of Cd-resistant mice. These observations suggest that the microvasculature in livers of inbred mice is the target tissue responsible for strain-dependent susceptibility to Cd-induced liver injury. The mechanisms that account for this genetic variation in endothelial cell response to Cd are unknown, but do not appear to be related to the cellular disposition of Cd nor to a defect in the metabolism of MT.
小鼠近交系对镉（Cd）肝毒性的易感性存在差异。例如，C3H/HeJ小鼠对Cd诱导的肝毒性敏感，而DBA/2J小鼠具有抗性。Cd肝毒性遗传易感性的机制尚不清楚。一种关于急性靶器官中毒的当代理论认为，Cd最初损伤血管内皮，实质细胞损伤是局部缺血导致的继发事件。在本研究中，对C3H小鼠肝内皮细胞（EC）比DBA小鼠的肝内皮细胞对Cd毒性更敏感这一假说进行了验证。肝实质细胞和内皮细胞在单层培养中分别生长22小时，随后用不同浓度的Cd处理。通过乳酸脱氢酶泄漏和细胞内K+流失评估肝细胞毒性，而通过台盼蓝排斥和蛋白质合成抑制评估内皮细胞损伤。各品系肝细胞对Cd细胞毒性作用的易感性相同。相比之下,内皮细胞对Cd中毒的易损性具有品系依赖性。当暴露于2.5 - 10.0 microM Cd时，Cd敏感小鼠的内皮细胞比Cd抗性小鼠的内皮细胞对Cd的细胞毒性作用更敏感。两个品系中内皮细胞的基础金属硫蛋白（MT）水平以及Cd摄取相似。Cd暴露后，Cd敏感小鼠的内皮细胞积累的MT量与Cd抗性小鼠的内皮细胞相似。这些观察结果表明，近交系小鼠肝脏中的微血管是导致品系依赖性Cd诱导肝损伤易感性的靶组织。导致内皮细胞对Cd反应出现这种遗传变异的机制尚不清楚，但似乎与Cd的细胞分布以及MT代谢缺陷无关。
