雷公藤内酯醇的遗传毒性评价

目的 观察雷公藤的主要有效成分之一雷公藤内酯醇的遗传毒性。方法 采用鼠伤寒沙门氏菌回复突变试验(Ames试验)、体外培养CHO细胞染色体畸变试验和小鼠骨髓微核试验检测雷公藤内酯醇的遗传毒性。结果 Ames试验提示在每皿1.6~1000 μg受试剂量下,在加或不加S9代谢活化系统时,受试物对组氨酸缺陷型鼠伤寒沙门氏菌TA97、TA98、TA100、TA102及TA1535所诱发的回复突变菌落数均与溶媒对照的突变菌落数相近。体外培养CHO细胞染色体畸变试验结果显示0.01、0.02和0.04 μg/ml 3个剂量的受试物,对加与不加S9代谢活化系统培养的CHO细胞的染色体畸变率无明显影响。小鼠骨髓微核试验设180、360、720 μg/kg 3个剂量,在720 μg/kg剂量时,雷公藤内酯醇有诱发骨髓嗜多染红细胞微核率增高的效应。结论 在本实验条件下,雷公藤内酯醇对鼠伤寒沙门氏菌无致突变性,对哺乳动物培养细胞染色体无致畸变作用,720 μg/kg剂量下对ICR小鼠有诱发骨髓嗜多染红细胞微核率增高的效应。提示雷公藤内酯醇对人体可能具有潜在的遗传毒性。     

鼠尾草酸的遗传毒性研究

目的 研究鼠尾草酸(carnosic acid,CA)的遗传毒性。方法 选用鼠伤寒沙门杆菌回复突变(Ames 试验)、体内哺乳动物红细胞微核、精子畸形以及单细胞凝胶电泳(彗星试验)四项致突变生物学试验进行筛选评价。结果 在6.25～50μg/mL 的剂量水平,CA 对鼠伤寒沙门菌株TA97、TA98、TA100、TA102 和TA1535 均无诱变性;此外,在受试剂量下小鼠骨髓嗜多染红细胞微核、小鼠精子畸形以及体内彗星试验的结果均为阴性(与溶剂对照比较,P> 0.05)。结论 在本实验条件下,CA 未见明显遗传毒性。     

补血益母丸遗传毒性研究

目的 对补血益母丸干膏粉进行遗传毒性试验,为临床安全用药提供依据。方法 采用组氨酸营养缺陷型鼠伤寒沙门氏菌TA97a、TA98、TA100、TA102、TA1535进行细菌回复突变（Ames）试验,采用中国仓鼠肺成纤维（CHL）细胞进行体外染色体畸变试验,采用ICR小鼠进行骨髓细胞微核试验综合评估补血益母丸干膏粉的遗传毒性。其中,Ames试验设50、150、500、1 500、5 000 μg·皿^-1 5个剂量;体外细胞染色体畸变试验设125、250、500 μg·mL^-1 3个剂量;小鼠骨髓细胞微核试验设500、1 000、2 000 mg·kg^-1 3个剂量,每天给药1次,连续给药3 d。结果 在代谢及非代谢活化条件下（＋S9/-S9）,Ames试验结果 显示,补血益母丸干膏粉对各菌株均无明显或可重复的诱变性及抑菌性;体外CHL细胞染色体畸变试验结果显示,补血益母丸干膏粉对CHL细胞染色体结构畸变率未见有意义的升高;小鼠骨髓细胞微核试验结果显示,补血益母丸干膏粉对ICR小鼠骨髓细胞微核率无明显影响。结论 补血益母丸干膏粉未见潜在的遗传毒性。     

Wentilactone A的遗传毒性评价

目的 检测Wentilactone A的遗传毒性。方法 应用经典遗传毒性检测组合(Ames试验、体外培养CHO细胞染色体畸变试验和小鼠骨髓微核试验)检测Wentilactone A的遗传毒性。结果 Ames试验结果提示,Wentilactone A在每皿5 000、500、50、5、0.5 μg 5个剂量下,在加和不加代谢活化系统（S9）时,对鼠伤寒沙门菌均无致突变性。CHO细胞染色体畸变试验结果提示,在终浓度23.74、47.48、94.96 μg/ml 3个剂量组,在加和不加S9中,于作用4 h和24 h的条件下培养的CHO细胞,均未诱发染色体畸变。小鼠骨髓微核试验在100、200、400 mg/kg 3个剂量下作用24 h以及400 mg/kg剂量下作用48 h对骨髓细胞的微核诱发率,与溶剂对照组比较均无显著差异（P>0.05）。结论 Wentilactone A对鼠伤寒沙门菌无致突变性,对CHO细胞的染色体无致畸变作用,对ICR小鼠无诱发骨髓细胞微核的效应。上述结果提示Wentilactone A不具有遗传毒性和潜在致癌性。     

消旋酶法DL-丙氨酸的遗传毒性研究

目的 评价消旋酶法DL-丙氨酸的遗传毒性。方法 小鼠骨髓细胞微核实验设阴性对照组（纯水）、阳性对照组（环磷酰胺40 mg/kg）和消旋酶法DL-丙氨酸3个剂量组（10 000、5 000和2 500 mg/kg）,观察各组小鼠胸骨骨髓细胞微核发生率;小鼠精原细胞染色体畸变实验设阴性对照组（纯水）、阳性对照组（环磷酰胺40 mg/kg）和消旋酶法DL-丙氨酸3个剂量组（10 000、5 000和2 500 mg/kg）,观察各组小鼠睾丸精原细胞染色体畸变类型并计算畸变率。细菌回复突变实验（Ames实验）设空白对照组、溶剂对照组、阳性对照组和消旋酶法DL-丙氨酸5个剂量组（50、158、500、1 580、5 000 μg/皿和8、40、200、1 000、5 000 μg/皿）,计数各组回复突变菌落数。结果 小鼠骨髓细胞微核实验结果显示,各剂量组消旋酶法DL-丙氨酸微核细胞率与对照组的差异无统计学意义（P>0.05）;小鼠精原细胞染色体畸变实验结果显示,各剂量组消旋酶法DL-丙氨酸动物睾丸精原细胞染色体畸变率与对照组的差异无统计学意义（P>0.05）;细菌回复突变实验结果显示,在加或不加S9的情况下,各剂量组消旋酶法DL-丙氨酸对TA97a、TA98、TA100、TA102、TA1535菌株均无致突变作用,差异无统计学意义（P>0.05）。结论 消旋酶法DL-丙氨酸未见明显遗传毒性。     

复方山莨菪碱注射液的遗传毒性评价

目的 复方山莨菪碱注射液的遗传毒性研究。方法 采用细菌回复突变试验（bacterial reverse mutation test,简称Ames test）,体外染色体畸变试验（chromosome aberration test,简称CA）和体内微核试验（micronucleus test,简称MNT）3个标准试验组合,以评价复方山莨菪碱注射液的遗传毒性。结果 Ames试验表明在所有受试剂量为0.5、5、50、500、5 000μg/皿,两种平行条件下,即有或没有S9代谢活化系统时,受试物对TA1535、TA102、TA100、TA98及TA97这5种细菌菌株,与溶媒对照组的突变菌落数进行比较,各剂量组的所诱发的回复突变菌落数均与其相近。CA试验中,受试物设3个剂量组,依次为58.75、117.5及235.0μg/ml,所有剂量在两种平行的系统条件下（即有或没有S9代谢活化系统时）,对中国仓鼠卵巢细胞（CHO细胞）的染色体畸变率均没有显著影响。MNT试验也设了3个剂量组,分别为7.5、15.0及30.0 mg/kg。所有剂量组与溶媒对照组的微核诱发率进行比较,对ICR小鼠骨髓的微核诱...     

崖柏精油致突变作用研究

摘 要 目的：采用鼠伤寒沙门菌回复突变（AMES）试验和哺乳动物微核试验对崖柏精油的遗传毒性进行评价。方法: AMES试验采用TA97、TA98、TA100和TA102四种菌株,对崖柏精油的致突变性进行评价。采用小鼠骨髓噬多染红细胞微核试验,对本品的染色体毒性进行评价。结果: 崖柏精油不同剂量组对TA97、TA98、TA100、TA102四种试验菌株,在加大鼠肝微粒体酶S9和不加S9的情况下,回复突变数均不超过溶剂对照组的1倍,差异无统计学意义（P<0.05）,为诱变阴性。微核试验表明,崖柏精油各剂量组对小鼠骨髓微核率无显著影响（P>0.05）。结论:崖柏精油无明显遗传毒性。     

银参胶囊遗传毒性研究

目的探讨银参胶囊的遗传毒性。方法选用SPF级健康ICR小鼠,通过Ames试验、小鼠骨髓细胞微核试验、小鼠睾丸染色体畸变试验等遗传毒性试验验证银参胶囊的安全性。结果 Ames试验中,银参胶囊在8~5 000μg/皿剂量范围内,无论是否加入哺乳动物肝脏微粒体酶(S9),鼠伤寒沙门菌TA97,TA98,TA100,TA102等4株菌的回复突变菌落数均未出现剂量依赖性增加;微核试验中,2 500,5 000,10 000 mg/kg剂量组均未见骨髓中含微核的嗜多染红细胞数增加;小鼠睾丸染色体畸变试验中,药物质量分数为2 500,5 000,10 000 mg/kg时,细胞的染色体畸变率均未出现剂量依赖性增加。结论银参胶囊未显示致突变作用,可初步判定其在遗传毒性方面是安全的。     

蝉花孢梗束的毒性研究

目的 对人工培植的蝉花孢梗束进行毒理学研究,评价其口服安全性。方法 利用急性毒性试验、体外中国仓鼠肺细胞染色体畸变试验、骨髓细胞微核试验、鼠伤寒沙门氏菌回复突变试验和孕鼠致畸试验进行毒理学评价。结果 急性毒性试验结果表明蝉花孢梗束对雌、雄大鼠急性经口最大耐受量（MTD）均>10 g/kg,属于无毒级;中国仓鼠肺细胞染色体畸变试验、骨髓细胞微核试验、鼠伤寒沙门氏菌回复突变试验以及3项遗传毒性试验的结果皆为阴性,未显示致突变性;蝉花孢梗束各剂量组在大鼠孕期体质量、死胎率、吸收胎率与阴性对照组比较差异无显著性（P>0.05）,各剂量组胎鼠质量、胎鼠身长、前囟宽度与阴性对照组比较差异无显著性（P>0.05）;各剂量组在胎鼠外观、内脏发育、骨骼发育检查上与阴性对照组比较差异无显著性（P>0.05）。结论 在本研究条件下,未见蝉花孢梗束有急性毒性、遗传毒性,对孕鼠无致畸作用,具有良好的安全性。     

聚乙二醇修饰降纤酶的遗传毒性评价

目的检测聚乙二醇修饰降纤酶的遗传毒性。方法应用鼠伤寒沙门菌回复突变试验(Ames试验)、体外培养CHO细胞染色体畸变试验和小鼠骨髓微核试验检测聚乙二醇修饰降纤酶的遗传毒性。结果 Ames试验结果显示每平皿100、20、4、0.8、0.16 U各个剂量组,在加或不加S9代谢活化系统时对组氨酸缺陷型鼠伤寒沙门菌TA97、TA98、TA100、TA102及TA1535所诱发的回复突变菌落数均与溶剂对照的突变菌落数相近。体外培养CHO细胞染色体畸变试验结果显示2.5、5.0和10.0 U.mL-1各个剂量组在加S9代谢活化系统于24 h和不加S9代谢活化系统于24 h、48 h培养的CHO细胞染色体畸变率与溶剂对照组比较均无显著差异(P>0.05)。小鼠骨髓微核试验显示425、850、1700 U.kg-1各个剂量组对ICR小鼠的微核诱发率与溶剂对照组比较均无显著差异(P>0.05)。结论聚乙二醇修饰降纤酶对鼠伤寒沙门菌无致突变性,对哺乳动物培养细胞的染色体无致畸变作用,对ICR小鼠无诱发骨髓嗜多染红细胞微核的效应。表明聚乙二醇修饰降纤酶在本实验条件下无遗传毒性。     

米索前列醇的急性毒性和长期毒性

小鼠皮下注射和灌胃米索前列醇(Mis)的LD_(50)分别是37.1和56.4mg/kg。大鼠灌胃Mis0.6,2和6mg/(kg·d)30d,红细胞和血红蛋白升高,血糖和总蛋白量降低(均在正常范围);前列腺的脏器系数减小。撤药d15,上述改变均恢复到对照水平。病理检查示Mis导致曲精细管上皮严重受损,生精细胞减少至消失,尤以6mg/(kg·d)组为甚,撤药d15生精细胞增多。提示长期大量应用Mis对雄性生殖系统产生可逆性损伤。     

Subchronic toxicity,toxicity to reproduction and prenatal developmental toxicity of vinyl laurate

Vinyl laurate (VL), is used in the manufacture of polyvinyl acetate vinyl laurate copolymer a component of gum base for chewing gum production. The potential toxicity of VL to reproduction was examined in a combined repeated dose and reproduction/developmental toxicity screening study (OECD test guideline 422) and a prenatal developmental toxicity screening study (OECD test guideline 414). VL was administered to Wistar rats by gavage at 0 (controls), 50, 250 and 1000 mg/kg bw/d. There were no signs of systemic toxicity in the parental animals of either study. Adverse effects on reproductive performance and fetal development that could be attributed to the VL treatment were not observed. Thus, the highest dose level tested was a NOAEL in these two studies.     

薏苡仁多糖急性毒性及遗传毒性试验研究

目的了解薏苡仁多糖的毒理学安全性。方法小鼠急性毒性试验和遗传毒性试验（Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验）。结果薏苡仁多糖的小鼠经口LD50〉20g·kg^-1;在Ames试验、小鼠骨髓嗜多染红细胞微核试验、小鼠精子畸形试验中均呈阴性反应,未显示有遗传毒性作用。结论薏苡仁多糖基本无毒性。     

Glutathione-dependent toxicity

1. Recent studies show that glutathione conjugate formation is an important bioactivation mechanism for several groups of compounds with implications for organ-selective toxicity and carcinogenicity.

2. Vicinal dihaloalkanes, such as 1,2-dihaloethanes, yield S-(2-haloalkyl)glutathione conjugates that give rise to highly electrophilic episulphonium ions, which are involved in the cytotoxicity and mutagenicity of 1,2-dihaloethanes.

3. Nephrotoxic haloalkenes are metabolized to S-(haloalkenyl)- or S-(haloalkyl)-glutathione conjugates which, after metabolism to the corresponding cysteine conjugates, are bioactivated by renal cysteine conjugate β-lyase to yield cytotoxic or mutagenic metabolites.

4. Finally, hepatic glutathione conjugate formation with hydroquinones and amino-phenols yields conjugates that are directed to γ-glutamyltransferase-rich tissues, such as the kidney, where they undergo alkylation or redox cycling reactions, or both, that cause organ-selective damage.     

Digitalis toxicity

The principal causes of digitalis toxicity are overdose, reduced volume of distribution, reduced renal elimination, and increased myocardial sensitivity. The metabolic mechanism of digitalis toxicity is intense inhibition of sarcolemma Na-K ATPase, which leads to increases of intracellular Na+ and Ca2+ and arrhythmogenic membrane ionic currents. A variety of cellular electrophysiologic effects and effects on the nervous system are responsible for the array of clinical arrhythmias seen during digitalis toxicity, i.e., sinus bradycardia, atrioventricular block, nonparoxysmal atrioventricular junctional tachycardia, and ventricular tachycardia.     

Naphthalene-induced respiratory tract toxicity: metabolic mechanisms of toxicity

The lung, which is in intimate contact with the external environment, is exposed to a number of toxicants both by virtue of its large surface area and because it receives 100% of the cardiac output. Lung diseases are a major disease entity in the U.S. population ranking third in terms of morbidity and mortality. Despite the importance of these diseases, key issues remain to be resolved regarding the interactions of chemicals with lung tissue and the factors that are critical determinants of chemical-induced lung injury. The importance of cytochrome P450 monooxygenase dependent metabolism in chemical-induced lung injury in animal models was established over 25 years ago with the furan, 4-ipomeanol. Since then, the significance of biotransformation and the reasons for the high degree of pulmonary selectivity for a myriad of different chemicals has been well documented, mainly in rodent models. However, with many of these chemicals there are substantial differences in the susceptibility of rats vs. mice. Even within the same species, varied levels of the respiratory tract respond differently. Thus, key pieces of data are still missing when evaluating the applicability of data generated in rodents to primates, and as a result of this, there are substantial uncertainties within the regulatory community with regards to assessing the risks to humans for exposure to some of these chemicals. For example, all of the available data suggest that the levels of cytochrome P450 monooxygenases in rodent lungs are 10-100 times greater than those measured in the lungs of nonhuman primates or in man. At first glance, this suggests that a significant margin of safety exists when evaluating the applicability of rodent studies in the human, but the issues are more complex. The intent of this review is to outline some of the work conducted on the site and species selective toxicity and metabolism of the volatile lung toxic aromatic hydrocarbon, naphthalene. We argue that a complete understanding of the cellular and biochemical mechanisms by which this and other lung toxic compounds generate their effects in rodent models with subsequent measurement of these cellular and biochemical events in primate and human tissues in vitro will provide a far better basis for judging whether the results of studies done in rodent models are applicable to humans.