Templin M V, Jamison K C, Wolf D C, Morgan K T, Butterworth B E
Chemical Industry Institute of Toxicology, Research Triangle Park, NC 27709-2137, USA.
Cancer Lett. 1996 Jun 24;104(1):71-8. doi: 10.1016/0304-3835(96)04234-6.
Chloroform given by gavage in corn oil at 180 mg/kg per day induced kidney tumors in male Osborne-Mendel rats. Chloroform-induced cytotoxicity and regenerative cell proliferation have been observed in the kidneys of male F-344 rats. In order to compare the acute sensitivity of male Osborne-Mendel with F-344 rats, animals from both strains were administered a single gavage dose of 0, 10, 34, 90, 180, or 477 mg/kg chloroform and necropsied 48 h later. Known target tissues were examined for histological changes. Regenerative cell proliferation was assessed as a labeling index (LI, percent of cells in S-phase) as determined by nuclear incorporation of bromodeoxyuridine. The epithelial cells of the proximal tubules of the kidney cortex were the primary target cells for cytotoxicity and regenerative cell proliferation. A dose-dependent increase in the LI was present in the kidney of Osborne-Mendel rats given doses of 10 mg/kg chloroform and above and in F-344 rats given 90 mg/kg and above. The maximal increase in the LI was 4.5- or 3.7-fold over control in Osborne-Mendel or F-344 given 477 mg/kg, respectively. The only increase in the hepatocyte LI was in the F-344 rats given 477 mg/kg. Edema and periosteal hypercellularity were observed in the nasal passages of both strains at doses of 90 mg/kg and above. These data indicate that Osborne-Mendel and F-344 rats are about equally susceptible to chloroform-induced nephrotoxicity. These results provide a basis for linking the extensive data base on mechanisms of action of chloroform toxicity in F-344 rats to the Osborne-Mendel rat and support the hypothesis that events secondary to chloroform-induced cytolethality and regenerative cell proliferation played a role in the induction of renal tumors in the Osborne-Mendel rat.
每天以180毫克/千克的剂量通过玉米油灌胃给予氯仿，可诱导雄性奥斯本-孟德尔大鼠发生肾肿瘤。在雄性F-344大鼠的肾脏中已观察到氯仿诱导的细胞毒性和再生细胞增殖。为了比较雄性奥斯本-孟德尔大鼠与F-344大鼠的急性敏感性，给两个品系的动物单次灌胃给予0、10、34、90、180或477毫克/千克的氯仿，并在48小时后进行尸检。检查已知的靶组织是否有组织学变化。通过溴脱氧尿苷的核掺入将再生细胞增殖评估为标记指数（LI，S期细胞百分比）。肾皮质近端小管的上皮细胞是细胞毒性和再生细胞增殖的主要靶细胞。给予10毫克/千克及以上氯仿剂量的奥斯本-孟德尔大鼠和给予90毫克/千克及以上氯仿剂量的F-344大鼠的肾脏中，LI呈剂量依赖性增加。给予477毫克/千克氯仿的奥斯本-孟德尔大鼠或F-344大鼠中，LI的最大增幅分别比对照组高4.5倍或3.7倍。肝细胞LI唯一的增加出现在给予477毫克/千克氯仿的F-344大鼠中。在两个品系中，给予90毫克/千克及以上剂量时，鼻道中均观察到水肿和骨膜细胞增多。这些数据表明，奥斯本-孟德尔大鼠和F-344大鼠对氯仿诱导的肾毒性的易感性大致相同。这些结果为将关于F-344大鼠氯仿毒性作用机制的大量数据库与奥斯本-孟德尔大鼠联系起来提供了基础，并支持以下假设：氯仿诱导的细胞致死率和再生细胞增殖继发的事件在奥斯本-孟德尔大鼠肾肿瘤的诱导中起作用。
