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981.
H Yamazaki Y Oda Y Funae S Imaoka Y Inui F P Guengerich T Shimada 《Carcinogenesis》1992,13(6):979-985
The possible roles of cytochrome P450 (P450) enzymes in the metabolic activation of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) by rat liver microsomes have been examined in a system containing the bacterial tester strain Salmonella typhimurium NM2009, a newly developed strain showing high O-acetyltransfer activities. The DNA-damaging activity could be determined by measuring expression of the umu gene in a plasmid containing the fused umuC-lacZ gene construct in the bacteria. The following lines of evidence support the view that both NDMA and NDEA are principally oxidized to reactive products by P450 2E1 in rat liver microsomes. First, NDMA and NDEA were activated by rat liver microsomes in a protein- and substrate-dependent manner and the former chemical was more active than the latter; both activities were induced in rats treated with P450 2E1 inducers such as ethanol, acetone and isoniazid and by starvation. Second, activation of NDMA and NDEA were both inhibited significantly by antibodies raised against rat P450 2E1 and by P450 2E1 inhibitors such as diethyldithiocarbamate and 4-methylpyrazole in rat liver microsomes. Finally, in reconstituted monooxygenase systems containing purified rat P450 enzymes, P450 2E1 gave the highest rates of the activation of both NDMA and NDEA; the addition of rabbit cytochrome b5 to the system caused about a 1.5-fold increase in both reactions. In separate experiments we also found that N-nitrosomethylacethoxymethylamine, a compound that reacts with DNA after ester cleavage, is more genotoxic in S.typhimurium NM2009 than in S.typhimurium NM2000, a strain that is defective in O-acetyltransferase activity. Part of the pathway involved in the activation of nitrosamines is suggested to be acetylation of alkyldiazohydroxides formed by P450 or acetylesterase, because the genotoxic activity of N-nitrosomethylacethoxymethylamine in S.typhimurium NM2009 could be inhibited by the O-acetyltransferase inhibitor pentachlorophenol. These results indicate that NDMA and NDEA are oxidized to gentoxoic products by rat liver microsomes and that a P450 2E1 enzyme plays a major role in the activation of these two potent carcinogens. The activation pathway of N-nitrosodialkylamines through acetylation by O-acetyltransferase has been proposed. This simple bacterial system for measuring genotoxicity should facilitate studies on the activation of N-nitroso alkylamines. 相似文献
982.
The etiology of neuronal intestinal dysplasia remains largely unknown. There is, however, supporting evidence of the existence of Hirschprung's disease or chronic intestinal obstruction associated with neuronal intestinal dysplasia. With the aim of investigating the possible development of neuronal intestinal dysplasia linked to chronic intestinal obstruction, we have examined the enteric nervous system response to long-term obstruction in a rat model. Three different surgical techniques were tested in Wistar male rats. In animals that survived longer than the cutoff chronic intestinal obstruction point (6 weeks), full-thickness biopsies and acetylcholinesterase (AChE), NADH, hematoxylin-eosin, and anti-S100 protein stainings were performed. The results of our model indicate that chronic intestinal obstruction induced different degrees of enteric nervous system dysplasia, including histological features of neuronal intestinal dysplasia. The relationship between chronic intestinal obstruction and anomalies of the enteric nervous system, including neuronal intestinal dysplasia, needs to be further studied. 相似文献
983.
984.
A focal cerebral ischemic model was produced by occlusion of the intracranial main cerebral artery with a silicone cylinder in normotensive (NTR) and spontaneously hypertensive rats (SHR). Main cerebral artery could be successfully occluded in approximately 90%. The most frequent embolized site was the distal part of the internal cerebral artery (ICb) and less frequently the horizontal segment of the anterior cerebral artery (Al). Mortality rate of NTR with ICb occlusion (NTR-ICb) was 43% at 72 hours after embolization and that of SHR with ICb occlusion (SHR-ICb) was 67% at 24 hours after embolization. NTR-ICb showed neurological signs (i.e. circling movement, hemiparesis, poor response to pain stimuli) and histologically, showed infarction in the deep cerebral structures (i.e. thalamus, hypothalamus, hippocampus, and internal capsule) accompanied with mild disruption of blood-brain barrier (BBB). SHR-ICb showed more serious neurological signs and more severe cerebral infarction in the deep cerebral structures with severe disruption of BBB. In SHR-ICb, ischemic cerebral edema was more prominent which may deteriorate symptoms and pathological findings compared to NTR-ICb. This embolization model is proposed to be useful for studying the pathophysiology of focal cerebral ischemia, especially, early ischemic edema. 相似文献
985.
Y H Zhang 《中华神经精神科杂志》1986,19(3):170-174
986.
Isolation of a renal function-facilitating constituent from the Oriental drug, salviae miltiorrhizae radix 总被引:2,自引:0,他引:2
An attempt was made to isolate the active component which exhibits an improving effect on renal function from Salviae Miltiorrhazae Radix (Chinese crude drug). Systematic isolation from aqueous extract of Salviae Miltiorrhizae Radix was carried out, and Compound 1 was found to be more effective than any of the other constituents in improving renal functional parameters; that is, a marked reduction of glomerular filtration rate following adenine ingestion was improved by administration of this substance. The renal plasma flow and renal blood flow were also increased in renal failure rats. On the basis of chemical and spectroscopic data, Compound 1 was shown to be identical with magnesium lithospermate B. 相似文献
987.
988.
989.
990.
Smooth muscle relaxant effect of dehydroindicolactone 总被引:1,自引:0,他引:1
Dehydroindicolactone, a novel linear furanocoumarin with an 8-substituted side chain carrying a 5-member ring lactone, showed spasmolytic activity in a number of smooth muscle preparations. The spasmolytic activity seems to lie in its ability to block the dihydropyridine-sensitive calcium channel. 相似文献