Rodriguez R E, Misra M, Diwan B A, Riggs C W, Kasprzak K S
Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick Cancer Research and Development Center, Maryland 21702, USA.
Toxicology. 1996 Feb 22;107(2):131-40. doi: 10.1016/0300-483x(95)03251-a.
The aim of this study was to compare susceptibility of mice of different strains to the toxicity and carcinogenicity of nickel subsulfide (Ni3S2), a water insoluble compound suspected to damage cells through oxidative mechanisms. Groups of 30 male mice of each strain, C57BL/6 (C57BL), (C57BL x C3H/He)F1 (B6C3F1), and C3H/He (C3H), were injected with single doses of 0.5-10 mg of Ni3S2/site into the thigh muscle and observed for up to 78 weeks. The highest Ni3S2 dose was lethal within 1 week to C57BL (93%) > B6C3F1 (80%) > C3H (53%) mice. The most susceptible C57BL mice also had the most severe necrotic/inflammatory kidney damage, compared with that in the other mice. The final incidence of local sarcomas at the 5 mg Ni3S2 dose was: C3H (97%) > B6C3F1 (76%) > C57BL (40% of mice at risk, i.e. those surviving at least 25 week; P < 0.05 or better as compared to the incidence in C3H mice). The relatively highest acute toxicity of Ni3S2 in C57BL mice observed in the present study, concurred with the weakest antioxidant response to systemic water-soluble nickel(II), resulting in reduction in glutathione (GSH) level and increased lipid peroxidation (LPO) in their kidneys and livers, two main targets of acute nickel toxicity, reported by us previously (Toxicol. Lett. 1991, 57, 269; ibid. 1991, 58, 121). Ni3S2 deposited in the muscle, therefore, constitutes a source of soluble nickel that can reach and damage distant organs. THe strongest tumor response in C3H mice relative to other strains did, in turn, concur with the lowest base levels of GSH and highest LPO in their muscle, the target for Ni3S2 carcinogenesis. Thus, the acute toxicity and carcinogenicity of Ni3S2 and Ni3S2-derived soluble nickel(II) in mice seem to depend, at least in part, on antioxidant capacity of target organs, which varies among different strains.
本研究的目的是比较不同品系小鼠对硫化亚镍（Ni3S2）毒性和致癌性的易感性，Ni3S2是一种水不溶性化合物，被怀疑通过氧化机制损伤细胞。将每组30只各品系的雄性小鼠，即C57BL/6（C57BL）、（C57BL×C3H/He）F1（B6C3F1）和C3H/He（C3H），在大腿肌肉中单次注射0.5 - 10mg/kg的Ni3S2，并观察长达78周。最高剂量的Ni3S2在1周内对C57BL（93%）> B6C3F1（80%）> C3H（53%）小鼠具有致死性。与其他小鼠相比，最易感的C57BL小鼠还具有最严重的坏死/炎性肾损伤。在5mg/kg Ni3S2剂量下局部肉瘤的最终发生率为：C3H（97%）> B6C3F1（76%）> C57BL（有风险的小鼠中的40%，即至少存活25周的小鼠；与C3H小鼠的发生率相比，P < 0.05或更好）。在本研究中观察到Ni3S2在C57BL小鼠中具有相对较高的急性毒性，这与它们对全身水溶性镍（II）的最弱抗氧化反应一致，导致其肾脏和肝脏中的谷胱甘肽（GSH）水平降低和脂质过氧化（LPO）增加，这两个是我们之前报道的急性镍毒性的主要靶器官（《毒理学快报》1991年，57卷，269页；同上，1991年，58卷，121页）。因此，沉积在肌肉中的Ni3S2构成了可溶性镍的来源，其可以到达并损伤远处器官。相对于其他品系，C3H小鼠中最强的肿瘤反应又与它们肌肉中最低的GSH基础水平和最高的LPO一致，肌肉是Ni3S2致癌作用的靶器官。因此，Ni3S2及其衍生的可溶性镍（II）在小鼠中的急性毒性和致癌性似乎至少部分取决于靶器官的抗氧化能力，而这在不同品系中有所不同。
