Kasprzak K S, Diwan B A, Rice J M
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, MD 21702.
Toxicology. 1994 May 31;90(1-2):129-40. doi: 10.1016/0300-483x(94)90211-9.
Effects of magnesium basic carbonate (MgCarb) and metallic iron powder (Fe0) on nickel subsulfide (Ni3S2)-induced carcinogenesis were studied in kidneys of male F344/NCr rats. The rats, 20-40/group, received injections of Ni3S2 alone (62 mumol Ni) or with equimolar doses of MgCarb or Fe0 into the renal cortex of each pole of the right kidney. Control rats were given MgCarb, Fe0, or 0.1 ml of 50% aqueous glycerol, the injection vehicle. Final incidence of renal tumors 2 years after the injection of Ni3S2 alone or mixed with Fe0 was 60%. However, rats given Ni3S2 + Fe0 developed renal tumors much more rapidly. In contrast, the incidence of renal tumors in rats given Ni3S2 + MgCarb was only 20% (P < 0.01 vs. Ni3S2 alone). No kidney tumors were observed in the control rats. Between weeks 4 and 32 post injection, Ni3S2 alone caused erythrocytosis. This effect was attenuated by Fe0, but not by MgCarb. Hence, there is no firm correlation between carcinogenic activity of nickel and its ability to induce erythropoiesis. All kidney tumors were of mesenchymal cell origin and resembled the sarcomatous variant of the classic rat renal mesenchymal tumor. Some of them metastasized to the lungs and other organs. In 3-35 days post-injection, kidneys of rats treated with Ni3S2 alone showed moderate to extensive necrosis, inflammation, fibrosis, and degenerative and regenerative proliferative changes in the proximal tubular epithelium at the injection site. Similar, but more severe and multifocal changes were observed in the kidneys of Ni3S2 + Fe0-treated rats. The necrosis was less severe in kidneys injected with Ni3S2 + MgCarb, but fibrosis and degenerative and regenerative changes in proximal tubular epithelium were similar to those observed in other treatment groups. Ni3S2 deposits were seen inside macrophages and proximal tubular epithelial cells of Ni3S2 and Ni3S2+ Fe0-treated kidneys more frequently than in Ni3S2 + MgCarb-treated kidneys. Thus, magnesium antagonizes nickel carcinogenesis in the rat kidney while iron tends to enhance it. This result may be related to respectively attenuating or enhancing effects of magnesium and iron on the inflammatory response to Ni3S2.
在雄性F344/NCr大鼠的肾脏中研究了碱式碳酸镁（MgCarb）和金属铁粉（Fe0）对硫化亚镍（Ni3S2）诱导致癌作用的影响。每组20 - 40只大鼠，分别接受单独注射Ni3S2（62 μmol Ni）或与等摩尔剂量的MgCarb或Fe0一起注射到右肾两极的肾皮质中。对照大鼠注射MgCarb、Fe0或0.1 ml 50%的甘油水溶液（注射媒介物）。单独注射Ni3S2或与Fe0混合注射2年后肾肿瘤的最终发生率为60%。然而，注射Ni3S2 + Fe0的大鼠肾肿瘤发展得更快。相比之下，注射Ni3S2 + MgCarb的大鼠肾肿瘤发生率仅为20%（与单独注射Ni3S2相比，P < 0.01）。对照大鼠未观察到肾肿瘤。在注射后第4周和第32周之间，单独注射Ni3S2导致红细胞增多症。Fe0可减弱这种作用，但MgCarb无此作用。因此，镍的致癌活性与其诱导红细胞生成的能力之间没有确定的相关性。所有肾肿瘤均起源于间充质细胞，类似于经典大鼠肾间充质肿瘤的肉瘤变体。其中一些转移到了肺和其他器官。在注射后3 - 35天，单独用Ni3S2处理的大鼠肾脏在注射部位出现中度至广泛的坏死、炎症、纤维化以及近端肾小管上皮的退行性和再生性增殖变化。在注射Ni3S2 + Fe0的大鼠肾脏中观察到类似但更严重和多灶性的变化。注射Ni3S2 + MgCarb的大鼠肾脏坏死较轻，但近端肾小管上皮的纤维化以及退行性和再生性变化与其他治疗组相似。在注射Ni3S2和Ni3S2 + Fe0的大鼠肾脏的巨噬细胞和近端肾小管上皮细胞内比注射Ni3S2 + MgCarb的大鼠肾脏更频繁地见到Ni3S2沉积物。因此，镁可拮抗大鼠肾脏中的镍致癌作用，而铁则倾向于增强这种作用。这一结果可能分别与镁和铁对Ni3S2炎症反应的减弱或增强作用有关。
