大蒜素对二甲基亚硝胺诱发的肝纤维化大鼠的保护作用

目的　研究大蒜素对实验性肝纤维化大鼠的保护作用。方法　 SD大鼠随机分为 5组 :正常对照组、模型组(给等量蒸馏水 )、大蒜素 (11、2 2 mg/ kg)组、秋水仙碱 (0 .15 g/ kg)组。二甲基亚硝胺 (DMN)诱发大鼠肝纤维化模型 ,各组在造模开始时 ig给药 ,实验共进行 4 2 d。腹主动脉取血 ,制备血清 ,进行肝功能、血脂、肝细胞病理学检查。结果　大蒜素各组均能明显降低实验性肝纤维化大鼠血清丙氨酸转氨酶 (AL T)、谷草转氨酶 (AST) (P<0 .0 5、0 .0 1)水平 ,以大蒜素 2 2 mg/ kg组作用明显 ,而秋水仙碱对肝功能没有明显的改善作用 (P>0 .0 5 )。大蒜素均能明显降低血清甘油三酯 (TG)、胆固醇 (TC)水平 ,提高血清白蛋白 (AL B)含量。病理学检查结果 ,大蒜素组肝细胞的坏死、空泡变性、出血及脂肪沉积较模型组和秋水仙碱组明显减轻 ,炎症细胞明显减少。电镜检查结果显示 ,大蒜素 11mg/ kg组肝细胞坏死、自溶较模型组明显减轻 ,大蒜素 2 2 mg/ kg组肝细胞接近正常。结论　大蒜素对 DMN所致肝损伤具有保护作用。     

小柴胡汤对鼠实验性肝纤维化的影响

目的:探讨小柴胡汤对鼠肝纤维化的抑制作用及该抑制作用与活性伊东细胞间的相互关系。方法:分别腹腔注射二甲基亚硝基胺和猪血清复制两种肝纤维化动物模型并投予小柴胡汤观察其预防与治疗作用。结果:小柴胡汤可促进肝维生素 A 含量恢复;降低肝胶原含量和明显抑制肝前α-Ⅰ型胶原的基因表达;显著减少Ⅰ、Ⅲ型胶原在肝脏沉积,明显减少。α-平滑肌原纤维阳性的伊东细胞的数目。结论:小柴胡汤可防治鼠肝纤维化的发生与发展。     

Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats

Increased deposition of the extracellular matrix components, particularly collagen, is a central phenomenon in liver fibrosis. Stellate cells, the central mediators in the pathogenesis of fibrosis are activated by free radicals, and synthesize collagen. Melatonin is a potent physiological scavenger of hydroxyl radicals. Melatonin has also been shown to be involved in the inhibitory regulation of collagen content in tissues. At present, no effective treatment of liver fibrosis is available for clinical use. We aimed to test the effects of melatonin on dimethylnitrosamine (DMN)-induced liver damage in rats. Wistar albino rats were injected with DMN intraperitoneally. Following a single dose of 40 mg/kg DMN, either saline (DMN) or 100 mg/kg daily melatonin was administered for 14 days. In other rats, physiologic saline or melatonin were injected for 14 days, following a single injection of saline as control. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) levels were evaluated in blood and tissue homogenates. DMN caused hepatic fibrotic changes, whereas melatonin suppressed these changes in five of 14 rats (P < 0.05). DMN administration resulted in increased hydroxyproline and MDA levels, and decreased GSH and SOD levels, whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin functions as a potent fibrosuppressant and antioxidant, and may be a therapeutic choice.     

N-nitrosodimethylamine,nitrate and nitrate-reducing microorganisms in human milk

Of 54 milk samples from 54 healthy nursing women analysed for volatile N-nitrosamines, 42 appeared negative. Trace amounts (below the detection limit 0.5 μgl^?1) of N-nitrosodimethylamine were detected in the milk of 10 mothers and two samples contained this compound at 1.1 and 1.2 μgl^?1 respectively. Almost all samples investigated contained nitrate (mean 2.9 ± 2.3 mgl^?1) and nitrate reducing microorganisms (mean 4.2 ± 1.0 log ml^?1). The recent finding of N-nitrosodimethylamine in human milk gives evidence of the continuous endogenous formation of N-nitrosamines.     

The mutagenicity of dialkyl nitrosamines in the salmonella plate assay

N-nitrosodimethylamine (DMN) is not mutagenic in the standard Salmonella plate incorporation assay (Ames test) in the presence of an in vitro metabolic activation system (S-9) derived from rat liver. When the S-9 was derived from Aroclor- or phenobarbital-induced mouse or hamster liver or from uninduced hamster liver, mutagenic activity was observed. Increasing the amount of S-9 above the usual maximum level of 50 μ1 per plate increased the mutagenic response. Similarly, the mutagenicity of N-nitrosodiethylamine (DEN) and N-nitrosodi(n-butyl)amine (DBN) was greater in the presence of hamster liver S-9 than when mouse or rat liver was used. Data are also presented indicating that the ability of rat liver S-9 to mediate the mutagenic activity of DMN in the “preincubation” assay is due to the fact that the various components are present in this assay at several times the concentrations attained in the standard plate incorporation assay.     

Editorial

Mass cultures of primary rat kidney cells were exposed briefly to aqueous solutions of 20 chemicals and their subsequent growth rate and mitotic activity measured. Proximate carcinogens, and some chemicals with a defined inhibitory action biochemically, depressed the growth and division of the cultures. Non-carcinogenic compounds and precarcinogens did not interfere with the subsequent growth rate and mitotic activity of the cultures. It is suggested that the possession of growth inhibitory properties could give an indication of the carcinogenic activity of a chemical on a short-term basis.     

DNA repair synthesis in primary cultures of kidneys from BALB/c and C3H mice treated with dimethylnitrosamine

A combined 'in vivo--in vitro' autoradiographic method was employed to examine the DNA repair induced in the kidney by a single dose of dimethylnitrosamine (DMNA). Unscheduled DNA synthesis was found to be dose-dependent in primary kidney cultures of DMNA-treated mice, and practically not detectable in controls. Its amount was positively correlated with the different susceptibility of C3H and BALB/c mice to kidney tumor induction by DMNA. This experimental model appears sensitive and able to provide repeatable results. It may be useful to detect the organotropic activity of a carcinogen toward the kidney.     

丹参提取物对CCl4和DMN诱导的大鼠肝纤维化的影响

分别采用四氯化碳和二甲基亚硝胺诱导的大鼠肝纤维化模型,以秋水仙碱和丹参作对照,通过肝组织病理学及Ⅰ、Ⅲ型胶原免疫组化观察,肝组织羟脯氨酸、丙二醛及血清肝功能部分指标检测,探讨丹提取物和治疗肝纤维化的效果及部分作用机理。     

Lead acetate does not inhibit dimethylnitrosamine activation and interacts with phenobarbital which is genotoxic in the ST cross of the Drosophila wing spot test

Lead acetate (PbAc) is known to inhibit the synthesis of the heme group, needed for hemeproteins like Cytochromes P450 (CYP450s). Dimethylnitrosamine (DMN) requires metabolic activation by CYP450s. The Drosophila wing spot test was performed to establish whether PbAc inhibits DMN activation in the standard (ST) and high bioactivation (HB) crosses, with different levels of CYP450s. Phenobarbital (PH) was used as an antagonist for its ability to induce CYP450s synthesis. PbAc (0.01, 0.1, 1.0 mM) produced significant small spots frequencies in the ST cross, indicating a possible genotoxic activity, however, the total spots frequency was negative at all concentrations. DMN (0.076 mM) was genotoxic in both crosses; surprisingly, PH (12 mM) was genotoxic and the PH-DMN treatment resulted synergic in the ST cross. Interestingly, the PbAc-PH pre-co-treatments showed a possible interaction in the ST cross. The GC-MS analysis showed a drop in the PH content as the PbAc concentration increased. PbAc also seemed to inhibit the genotoxic activity of PH, except at 0.01 mM. It is concluded that PbAc does not inhibit DMN activation by CYP450s in both crosses since it exerted a clear genotoxicity and that PH is genotoxic and interacts with PbAc in the ST but not the HB cross.