Mechanism of Protection against Aflatoxin Tumorigenicity in Rats Fed 5-(2-Pyrazinyl)-4-methyl-l,2-dithiol-3-thione (Oltipraz) and Related l,2-Dithiol-3-thiones and l
Mechanism of Protection against Aflatoxin Tumorigenicity in Rats Fed 5-(2-Pyrazinyl)-4-methyl-l,2-dithiol-3-thione (Oltipraz) and Related l,2-Dithiol-3-thiones and l
复制标题
饲喂 5-(2-吡嗪基)-4-甲基-1,2-二硫醇-3-硫酮（奥替普拉）及相关 1,2-二硫醇-3-硫酮和 l 的大鼠抗黄曲霉毒素致瘤性的机制
DOI：
--
复制
发表时间：
1987
期刊：
影响因子：
--
通讯作者：
B. Roebuck
中科院分区：
文献类型：
--
作者：
T. Kensler;P. Egner;P. Dolan;J. Groopman;B. Roebuck
1，2-二巯基-3-硫酮是一种五元环含硫化合物，具有抗氧化、化学治疗和化学保护活性，是十字花科蔬菜中的重要化学成分。饮食给予取代的1，2-二硫醇-3-甲硫氨酸，奥替普拉的作用|5-（2-吡嗪基）-4-甲基-1，2-二硫醇-3-基|，一种有效的抗肿瘤剂，在»fiatimi！在雄性F344大鼠中检查BI（AFBi）代谢、DNA加合物形成和肝肿瘤发生。给大鼠喂不同剂量的奥替普拉（0.01-0.1%）4周。在第二和第三周的oltipraz喂养大鼠灌胃250 «IG AFBi/kg每周五次。大鼠最终恢复到对照饮食1周后停止Al H，给药。在4个月时，通过对肝脏切片进行染色以确定肝细胞改变的局灶性区域，并对谷氨酰转肽酶活性进行定量。所有剂量的奥替普拉治疗均使7-谷氨酰转肽酶阳性病灶占据的肝脏体积减少>90%。在单次暴露于AFBi之前，在1周内喂食增加剂量的饮食奥替普拉（0.01-0.1%）的动物中，与肝DNA结合的AFBi水平降低40 - 80%。喂食较高水平的奥替普拉导致谷胱甘肽S-转移酶的比活性显著增加，可能有助于促进最终亲电形式AFBi（8，9-氧化物）的解毒。在低饮食浓度的奥替普拉（0.01%），唯一的诱导作用是对选定的细胞色素P-450单加氧酶的活动。因此，由奥替普拉提供的保护可能是由于亲电体解毒途径的增强以及MH 1的氧化代谢的改变。在肝线粒体后上清液的体外代谢研究中，低剂量奥替普拉预处理促进AFBi氧化产生黄曲霉毒素I '和Qi，但不促进MI。高剂量（0.1%）奥替普拉预处理增强AFBi向黄曲霉毒素IV M的初级代谢。和气以及氯仿不溶性代谢物的形成。用奥替普拉的一系列1，2-二巯基-3-硫酮和1，2-二巯基-3-酮衍生物进行的饲养研究表明，通过对1，2-二巯基-3-硫酮结构的微小修饰，可以容易地分离对细胞色素P-450依赖性单加氧酶和亲电解毒酶如谷胱甘肽·S ′-转移酶的诱导活性。未取代的1，2-二巯基-3-甲基环强烈诱导亲电解毒酶，但不是单加氧酶，并且是AFBi与肝DNA结合的最有效抑制剂。酶诱导作用的高效力、低毒性和选择性可使一些1，2-二硫醇-3-硫酮成为用于人类化学保护的优异化合物。
l,2-Dithiol-3-thiones, reported constituents of cruciferous vegetables, are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, and chemoprotective activities. The effects of dietary administration of a substituted l,2-dithiol-3-thione, oltipraz |5-( 2-pyrazinyl)-4-inethyl-l,2-dithiol-3-thione|, a potent antischistosomal agent, on »fiatimi! BI (AFBi) metabolism, DNA adduct formation, and hepatic tumorigenesis were examined in male F344 rats. Rats were fed graded doses of oltipraz (0.01-0.1%) for 4 wk. During the second and third wk of oltipraz feeding rats were gavaged with 250 «ig of AFBi/kg five times a wk. Rats were finally restored to control diet 1 wk after cessation of Al H, dosing. At 4 months focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for >-glutamyl transpeptidase activity. Treatment with oltipraz at all doses reduced by >90% the volume of liver occupied by 7-glutamyl transpeptidase-positive foci. levels of AFBi bound to hepatic DNA were reduced between 40 and 80% in animals fed increasing doses of dietary oltipraz (0.01-0.1%) for 1 wk prior to a single exposure to AFBi. Feeding of the higher levels of oltipraz led to marked increases in the specific activity of glutathione S-transferases, presumably serving to facilitate the detoxication of the ultimate electrophilic form of AFBi, the 8,9-oxide. At low dietary con centrations of oltipraz (0.01%), the only inductive effects seen were on the activities of selected cytochrome P-450 monooxygenases. Therefore, the protection afforded by oltipraz may be due to both the enhancement of electrophile detoxication pathways as well as modified oxidative metabolism of M H,. In in vitro metabolism studies with hepatic postmitochondrial supernatant, low-dose oltipraz pretreatment facilitated the oxidative production of aflatoxins I', and Qi, but not MI, from AFBi. High-dose (0.1%) oltipraz pretreatment enhanced the primary metabo lism of AFBi to aflatoxins IV M,. and Qi as well as the formation of chloroform-insoluble metabolites. Feeding studies with a series of 1,2dithiol-3-thioneand l,2-dithiol-3-one derivatives of oltipraz demonstrated that the inductive activity for cytochrome P-450-dependent monooxygen ases and electrophile detoxication enzymes, such as glutathione .S'-transferases, could be readily separated by minor modifications of the 1,2dithiol-3-thione structure. The unsubstituted l,2-dithiol-3-thione nucleus strongly induced electrophile detoxication enzymes, but not the monoox ygenases, and was the most effective inhibitor of the binding of AFBi to hepatic DNA Âinvivo. The high potency, low toxicity, and selectivity of enzyme inductive effects may render some of the l,2-dithiol-3-thiones as excellent compounds for chemoprotection in humans.
登录
查看更多内容
纯化的大鼠和仓鼠肝谷胱甘肽 S-转移酶对微粒体介导的黄曲霉毒素 B1 与 DNA 结合的影响。
影响因子：
9.7
作者：
Raj,HG;Prasanna,HR;Magee,PN;Lotlikar,PD
通讯作者：
Lotlikar,PD
饲喂乙氧基喹啉的大鼠中黄曲霉毒素代谢、黄曲霉毒素-N7-鸟嘌呤形成和肝肿瘤发生的调节：谷胱甘肽 S-转移酶的诱导作用。
影响因子：
11.2
作者：
Kensler,TW;Egner,PA;Davidson,NE;Roebuck,BD;Pikul,A;Groopman,JD
通讯作者：
Groopman,JD
大鼠和仓鼠肝脏中胞质谷胱甘肽 S-转移酶调节微粒体介导的黄曲霉毒素 B1 与外源和内源 DNA 的结合。
影响因子：
4.7
作者：
Lotlikar,PD;Jhee,EC;Insetta,SM;Clearfield,MS
通讯作者：
Clearfield,MS
用于估计横切面的微观肝细胞病灶数量的可靠体视学方法。
影响因子：
11.2
作者：
Pugh,TD;King,JH;Koen,H;Nychka,D;Chover,J;Wahba,G;He,YH;Goldfarb,S
通讯作者：
Goldfarb,S
生大豆分离蛋白增强胰腺癌发生：定量大鼠模型和营养考虑。
影响因子：
--
作者：
Roebuck,BD
通讯作者：
Roebuck,BD