制备异亚硝基丙二酸二乙酯的反应热安全分析和机理研究

本研究在丙二酸二乙酯和亚硝酸钠反应制备法匹拉韦中间体异亚硝基丙二酸二乙酯过程中,发现存在二次放热现象,并且亚硝酸钠的用量远超理论量.通过在线红外检测和反应热力学数据等对其反应过程进行了研究,探讨了二次放热原因,并解释了该反应机制,辨识出风险关键点,为该类亚硝化反应的研究提供了有力的安全数据支撑.     

Fat transforms ascorbic acid from inhibiting to promoting acid-catalysed N-nitrosation

Background

The major potential site of acid nitrosation is the proximal stomach, an anatomical site prone to a rising incidence of metaplasia and adenocarcinoma. Nitrite, a pre‐carcinogen present in saliva, can be converted to nitrosating species and N‐nitroso compounds by acidification at low gastric pH in the presence of thiocyanate.

Aims

To assess the effect of lipid and ascorbic acid on the nitrosative chemistry under conditions simulating the human proximal stomach.

Methods

The nitrosative chemistry was modelled in vitro by measuring the nitrosation of four secondary amines under conditions simulating the proximal stomach. The N‐nitrosamines formed were measured by gas chromatography–ion‐trap tandem mass spectrometry, while nitric oxide and oxygen levels were measured amperometrically.

Results

In absence of lipid, nitrosative stress was inhibited by ascorbic acid through conversion of nitrosating species to nitric oxide. Addition of ascorbic acid reduced the amount of N‐nitrosodimethylamine formed by fivefold, N‐nitrosomorpholine by >1000‐fold, and totally prevented the formation of N‐nitrosodiethylamine and N‐nitrosopiperidine. In contrast, when 10% lipid was present, ascorbic acid increased the amount of N‐nitrosodimethylamine, N‐nitrosodiethylamine and N‐nitrosopiperidine formed by approximately 8‐, 60‐ and 140‐fold, respectively, compared with absence of ascorbic acid.

Conclusion

The presence of lipid converts ascorbic acid from inhibiting to promoting acid nitrosation. This may be explained by nitric oxide, formed by ascorbic acid in the aqueous phase, being able to regenerate nitrosating species by reacting with oxygen in the lipid phase.     

胃癌高发区庄河县三种腌制食品的致突变性研究

应用Ａｍｅｓ试验对胃癌高发区庄河县三种腌制食品咸鱼干、咸猪肉及酸菜中可能存在的致突变物或致癌物进行了筛选。结果发现Ｎ－亚硝基化合物、苯并（ａ）芘、霉菌毒素、杂环胺类及一些其它致突变物在三种腌制食品中存在的可能性不大。但三种腌制食品亚硝化后均有较强的直接诱变性，提示该地区胃癌高发可能与食品中存在的致突变物前体有关系。     

Potential role of tryptophan derivatives in stress responses characterized by the generation of reactive oxygen and nitrogen species

To face physicochemical and biological stresses, living organisms evolved endogenous chemical responses based on gas exchange with the atmosphere and on formation of nitric oxide (NO(*)) and oxygen derivatives. The combination of these species generates a complex network of variable extension in space and time, characterized by the nature and level of the reactive oxygen (ROS) and nitrogen species (RNS) and of their organic and inorganic scavengers. Among the latter, this review focusses on natural 3-substituted indolic structures. Tryptophan-derived indoles are unsensitive to NO(*), oxygen and superoxide anion (O(2)(*-)), but react directly with other ROS/RNS giving various derivatives, most of which have been characterized. Though the detection of some products like kynurenine and nitroderivatives can be performed in vitro and in vivo, it is more difficult for others, e.g., 1-nitroso-indolic compounds. In vitro chemical studies only reveal the strong likelihood of their in vivo generation and biological effects can be a sign of their transient formation. Knowing that 1-nitrosoindoles are NO donors and nitrosating agents indicating they can thus act both as mutagens and protectors, the necessity for a thorough evaluation of indole-containing drugs in accordance with the level of the oxidative stress in a given pathology is highlighted.     

In vitro mutagenicity of rubber chemicals and their nitrosation products

14 chemicals employed in rubber manufacture were assayed in the Salmonella reversion test with the strains TA98 and TA100. Mixed diaryl-p-phenylenediamines were weakly mutagenic in TA98 after metabolic activation; poly-p-dinitrosobenzene was active in TA98 without as well as with S9. After in vitro reaction with nitrite at low pH, mixed diaryl-p-phenylenediamines became directly mutagenic in both strains, whereas poly-p-dinitrosobenzene retained its activity unchanged. Furthermore, 4 of the remaining chemicals acquired mutagenic characteristics: in the presence of S9, N,N'-dimethylpentyl-p-phenylenediamine reverted TA98 and hexamethylenetetramine reverted both TA98 and TA100; N-isopropyl-N'-phenyl-p-phenylenediamine was mutagenic in TA98 with and without S9; N-nitrosodiphenylamine was active in both strains without S9 and weakly mutagenic in TA98 after metabolic conversion.     

金线吊乌龟提取物的抗炎镇痛抗氧化和抑制亚硝化活性研究

目的：研究和比较金线吊乌龟Stephania cepharantha Hayata不同提取部位的抗炎、镇痛、抗氧化和抑制亚硝化活性。方法：采用二甲苯致小鼠耳廓肿胀法、醋酸扭体法和热板法考察金线吊乌龟不同提取部位的抗炎、镇痛活性;采用1,1-二苯基-2-三硝基苯肼(DPPH)自由基清除法和2,2-联氮基-双-(3-乙基苯并噻唑啉-6-磺酸)二铵盐(ABTS)自由基清除法测定金线吊乌龟不同提取部位的抗氧化活性;采用盐酸萘乙二胺法和α-萘胺法测定金线吊乌龟不同提取部位的抑制亚硝化活性。结果：与空白组小鼠比较,水提取物对耳廓肿胀抑制率为36.57%,扭体抑制率为49.14%,且给药后1、2 h小鼠对热板的痛阈值分别提高47.40%和67.35%,其余各组差异均具有统计学意义(P<0.05);乙酸乙酯提取物清除DPPH自由基[半数抑制浓度(IC₅₀)=(0.084±0.008) mg·mL^–1]和ABTS自由基[IC₅₀=(0.063±0.005) mg·mL^–1]的能力最强,并显著强于其他提取部位(P...     

二甲胺在体内形成二甲基亚硝胺的危险性—动力学研究

用正交试验分析了二甲胺(DMA)剂量、NaNO_2剂量以及给药方式对大鼠体内二甲基亚硝胺(NDMA)合成的影响。大鼠经口给予DMA125μmol和NaNO_225μmol,体内反应时间与DDMA产量之间的关系可用双曲线方程1/y=0.009886+0.0491/x来描述。DMA和NaNO_2剂量和NDMA产量关系的研究表明,NDMA产量与NaNO浓度的平方和DMA浓度呈正比。基于动力学研究的结果,本文讨论了实际可能摄入剂量的DMA和NaN0_2在人体内可能合成的NDMA数量。     

22种食品在亚硝化后的致突变性

本研究用Ames试验加预培养法检测了22种食品在亚硝化后的致突变性。22种食品包括6种酱油、2种鱼露、2种虾酱、2种香肠、6种鱼干、米面薄脆片、油炸猪皮、酱菜和食品香料。结果表明,16种食品对TA 100有直接致突变性。在本组样品中,虾酱具有最强的致突变性,它的特异致突性为37000个回变菌/g。用HPLC分析了一种前致癌物氨基对乙酚的含量。测得每克虾酱中的含量为439μg。食品在亚硝化后所具有的致突变性,提示了该食物内含有胺或酰胺化合物,它可在体内形成内源性致癌物—亚硝胺。因此,检测食品的致突变性,对防癌有一定意义。     

Competitive metabolism of L-arginine:arginase as a therapeutic target in asthma

Exhaled breath nitric oxide (NO) is an accepted asthma biomarker.Lung concentrations of NO and its amino acid precursor,L-arginine,are regulated by the relative expressions of the NO synthase (NOS) and arginase isoforms.Increased expression of arginase I and NOS2 occurs in murine models of allergic asthma and in biopsies of asthmatic airways.Although clinical trials involving the inhibition of NO-producing enzymes have shown mixed results,small molecule arginase inhibitors have shown potential as a therapeu...     

二甲胺在体内形成二甲基亚硝胺的危险性——催化和抑制作用的研究

本文报道了给予大鼠二甲胺(DMA)125μmol和NaNO_225μmol时,化学物质对DMA亚硝化的促进和抑制作用。硫氰酸钾(80和320μmol)和NaCl(250和1000μmol)对DMA亚硝化未见有促进作用。抗坏血酸(25μmol),L-脯氨酸(125μmol)和L-半胱氨酸(150umol)有效地阻断了二甲基亚硝胺(NDMA)合成,阻断率分别为88、89和87％。NDMA在饱食基础饲料的大鼠体内的合成显著低于空腹大鼠,降低80%。