Hietanen E, Bartsch H, Ahotupa M, Béréziat J C, Bussacchini-Griot V, Cabral J R, Camus A M, Laitinen M, Wild H
International Agency for Research on Cancer, Lyon, France.
Carcinogenesis. 1991 Apr;12(4):591-600. doi: 10.1093/carcin/12.4.591.
Groups of rats, either dosed with N-nitrosodiethylamine (NDEA) for 10 weeks (from the age of 7 to 17 weeks) or untreated, were fed diets containing either 2% (low fat, LF) or 30% polyunsaturated fat (high fat, HF) on an equicaloric basis from 5 weeks until rats were 43 weeks old. Biochemical parameters were measured during and at the end of the experiment in various organs, blood, urine and exhaled air, for correlation with the presence or absence of tumors. The HF diet tended to increase the number of hepatic tumors induced by NDEA, while the number of extrahepatic tumors was higher in rats fed on the LF diet; also the overall tumor incidence was higher in the LF group. In the HF/NDEA group, only two benign extrahepatic tumors were found. Plasma total and free cholesterol and triglyceride concentrations were lower in the HF than the LF group without NDEA treatment. In animals bearing liver and/or extrahepatic tumors all plasma lipid concentrations were lower than in tumor-free animals. Only minor or no changes were detected in blood catalase activity, malondialdehyde level, reduced glutathione (GSH) level or GSH-related enzymes and excretion of thioethers in the urine due to dietary modulation or NDEA. Changes in the liver that were associated with the HF diet were: (i) increased amounts of some polyunsaturated fatty acids and of total phospholipids in liver microsomes; (ii) an enhanced level of lipid peroxidation in liver; (iii) a decrease in liver glutathione levels during NDEA treatment, with a simultaneous adaptive increase in superoxide dismutase levels, and a decrease in renal glutathione levels in both treated and untreated groups; (iv) enhanced microsomal induction of aminopyrine N-demethylase and epoxide hydrolase activities by NDEA, and (v) decreased hexose monophosphate shunt (HMS) activity. All mono-oxygenase activities were lower, and the activities of epoxide hydrolase, UDP-glucuronosyltransferase and HMS were higher, in liver tumors than in non-tumorous liver of similarly-treated rats. Neither diet nor NDEA had a major effect on drug-metabolizing enzyme activities in lung and kidney. HF diet significantly increased ethane exhalation (an indicator of the whole-body pro-oxidant state) over those on the LF diet: in rats on either diet, it was further increased when NDEA was given. Ethane exhalation was still elevated 30 weeks after the cessation of NDEA treatment. Our results suggest an association between the observed changes in biochemical parameters, notably oxidative stress, due to dietary modulation and the altered tumor incidence and organ distribution of tumors induced by NDEA.
将大鼠分为两组，一组用N - 亚硝基二乙胺（NDEA）给药10周（从7周龄到17周龄），另一组不进行处理，从5周龄开始直至43周龄，两组大鼠均以等热量为基础，分别喂食含2%（低脂，LF）或30%多不饱和脂肪（高脂，HF）的饮食。在实验期间及结束时，测量各器官、血液、尿液和呼出气体中的生化参数，以与肿瘤的有无进行关联分析。高脂饮食倾向于增加由NDEA诱导的肝肿瘤数量，而低脂饮食喂养的大鼠肝外肿瘤数量更多；此外，低脂组的总体肿瘤发生率更高。在高脂/ NDEA组中，仅发现两个良性肝外肿瘤。在未用NDEA处理的情况下，高脂组的血浆总胆固醇、游离胆固醇和甘油三酯浓度低于低脂组。在患有肝和/或肝外肿瘤的动物中，所有血浆脂质浓度均低于无肿瘤动物。由于饮食调节或NDEA处理，在血液过氧化氢酶活性、丙二醛水平、还原型谷胱甘肽（GSH）水平或GSH相关酶以及尿液中硫醚排泄方面，仅检测到轻微变化或无变化。与高脂饮食相关的肝脏变化有：（i）肝微粒体中一些多不饱和脂肪酸和总磷脂的含量增加；（ii）肝脏中脂质过氧化水平增强；（iii）在NDEA处理期间肝脏谷胱甘肽水平降低，同时超氧化物歧化酶水平适应性增加，并且在处理组和未处理组中肾脏谷胱甘肽水平均降低；（iv）NDEA增强了微粒体中氨基比林N - 脱甲基酶和环氧化物水解酶的活性，以及（v）磷酸己糖旁路（HMS）活性降低。在肝肿瘤中，所有单加氧酶活性均低于相同处理的大鼠的非肿瘤肝脏，而环氧化物水解酶、UDP - 葡萄糖醛酸基转移酶和HMS的活性则更高。饮食和NDEA对肺和肾中的药物代谢酶活性均无重大影响。高脂饮食组的乙烷呼出量（全身促氧化状态的指标）显著高于低脂饮食组：在两种饮食喂养的大鼠中，给予NDEA后乙烷呼出量进一步增加。在停止NDEA处理30周后，乙烷呼出量仍升高。我们的结果表明，由于饮食调节导致的生化参数变化，特别是氧化应激，与NDEA诱导的肿瘤发生率改变和肿瘤器官分布之间存在关联。
