Badger D A, Kuester R K, Sauer J M, Sipes I G
Department of Pharmacology and Toxicology and Center for Toxicology, The University of Arizona, Tucson 85721, USA.
Toxicology. 1997 Aug 15;121(2):143-53. doi: 10.1016/s0300-483x(97)00065-6.
The Kupffer cell inhibitor, gadolinium chloride (GdCl3), protects the liver from a number of toxicants that require biotransformation to elicit toxicity (i.e. 1,2-dichlorobenzene and CCl4), as well as compounds that do not (i.e. cadmium chloride and beryllium sulfate). The mechanism of this protection is thought to result from reduced secretion of inflammatory and cytotoxic products from Kupffer cells (KC). However, since other lanthanides have been shown to decrease cytochrome P450 (P450) activity, the following studies were designed to determine if GdCl3 pretreatment alters hepatic P450 levels or activity. The toxicological relevance of GdCl3-mediated alterations in P450 activity was also estimated by determining the effect of GdCl3 pretreatment on the susceptibility of primary cultured hepatocytes to CCl4 and cadmium chloride (CdCl2). Male and female Sprague-Dawley rats were given GdCl3 (i.v., 10 mg/kg). Twenty-four hours later, livers were either processed for preparation of microsomes or for primary cultures of hepatocytes. Gadolinium chloride treatment reduced total hepatic microsomal P450 as well as aniline hydroxylase activity by approximately 30% in males and 20% in females. In hepatocytes isolated from rats pretreated with GdCl3, the toxicity caused by CCl4, but not CdCl2 was reduced. Interestingly, when GdCl3 was administered in vitro to microsomes, there was no effect on either the microsomal P450 difference spectra or p-hydroxylation of aniline. However, when GdCl3 was incubated with isolated hepatocytes, the cytotoxicity of CCl4 (but not CdCl2) was partially attenuated. These results suggest that, in addition to its inhibitory effects on KC, GdCl3 produces other effects which may alter the susceptibility of hepatocytes to toxicity caused by certain chemicals.
库普弗细胞抑制剂氯化钆（GdCl3）可保护肝脏免受多种需要生物转化才能产生毒性的毒物（如1,2 - 二氯苯和四氯化碳）以及无需生物转化的化合物（如氯化镉和硫酸铍）的侵害。这种保护机制被认为是由于库普弗细胞（KC）分泌的炎性和细胞毒性产物减少所致。然而，由于其他镧系元素已被证明会降低细胞色素P450（P450）的活性，因此开展了以下研究以确定GdCl3预处理是否会改变肝脏P450的水平或活性。通过测定GdCl3预处理对原代培养肝细胞对四氯化碳和氯化镉（CdCl2）敏感性的影响，还评估了GdCl3介导的P450活性改变的毒理学相关性。给雄性和雌性斯普拉格 - 道利大鼠静脉注射GdCl3（10 mg/kg）。24小时后，将肝脏用于制备微粒体或用于肝细胞原代培养。氯化钆处理使雄性大鼠肝脏微粒体总P450以及苯胺羟化酶活性降低约30%，雌性大鼠降低约20%。在用GdCl3预处理的大鼠分离出的肝细胞中，四氯化碳引起的毒性降低，但氯化镉引起的毒性未降低。有趣的是，当在体外将GdCl3应用于微粒体时，对微粒体P450差异光谱或苯胺的对羟基化均无影响。然而，当将GdCl3与分离的肝细胞一起孵育时，四氯化碳（而非氯化镉）的细胞毒性部分减弱。这些结果表明，除了对KC有抑制作用外，GdCl3还产生其他作用，可能会改变肝细胞对某些化学物质所致毒性的易感性。
