Kensler T W, Egner P A, Dolan P M, Groopman J D, Roebuck B D
Cancer Res. 1987 Aug 15;47(16):4271-7.
1,2-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 1,2-dithiol-3-thione, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione], a potent antischistosomal agent, on aflatoxin B1 (AFB1) 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 micrograms of AFB1/kg five times a wk. Rats were finally restored to control diet 1 wk after cessation of AFB1 dosing. At 4 months focal areas of hepatocellular alteration were identified and quantitated by staining sections of liver for gamma-glutamyl transpeptidase activity. Treatment with oltipraz at all doses reduced by greater than 90% the volume of liver occupied by gamma-glutamyl transpeptidase-positive foci. Levels of AFB1 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 AFB1. 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 AFB1, the 8,9-oxide. At low dietary concentrations 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 AFB1. In in vitro metabolism studies with hepatic post-mitochondrial supernatant, low-dose oltipraz pretreatment facilitated the oxidative production of aflatoxins P1 and Q1, but not M1, from AFB1. High-dose (0.1%) oltipraz pretreatment enhanced the primary metabolism of AFB1 to aflatoxins P1, M1, and Q1 as well as the formation of chloroform-insoluble metabolites. Feeding studies with a series of 1,2-dithiol-3-thione and 1,2-dithiol-3-one derivatives of oltipraz demonstrated that the inductive activity for cytochrome P-450-dependent monooxygenases and electrophile detoxication enzymes, such as glutathione S-transferases, could be readily separated by minor modifications of the 1,2-dithiol-3-thione structure. The unsubstituted 1,2-dithiol-3-thione nucleus strongly induced electrophile detoxication enzymes, but not the monooxygenases, and was the most effective inhibitor of the binding of AFB1 to hepatic DNA in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
1,2 - 二硫醇 - 3 - 硫酮是十字花科蔬菜的已知成分，是具有抗氧化、化疗和化学保护活性的五元环状含硫化合物。研究了膳食给予一种取代的1,2 - 二硫醇 - 3 - 硫酮奥替普拉[5 - (2 - 吡嗪基)-4 - 甲基 - 1,2 - 二硫醇 - 3 - 硫酮]，一种有效的抗血吸虫药，对雄性F344大鼠黄曲霉毒素B1（AFB1）代谢、DNA加合物形成和肝脏肿瘤发生的影响。大鼠喂食不同剂量的奥替普拉（0.01 - 0.1%），持续4周。在喂食奥替普拉的第二和第三周，大鼠每周5次灌胃给予250微克/千克的AFB1。在停止AFB1给药1周后，大鼠最终恢复到对照饮食。4个月时，通过对肝脏切片进行γ - 谷氨酰转肽酶活性染色来鉴定和定量肝细胞改变的局灶区域。所有剂量的奥替普拉处理使γ - 谷氨酰转肽酶阳性病灶所占肝脏体积减少超过90%。在单次暴露于AFB1之前，喂食不同剂量膳食奥替普拉（0.01 - 0.1%）1周的动物中，与肝脏DNA结合的AFB1水平降低了40%至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，这可能有助于促进AFB1的最终亲电形式8,9 - 环氧化物的解毒。在低膳食浓度的奥替普拉（0.01%）下，观察到的唯一诱导作用是对选定的细胞色素P - 450单加氧酶的活性。因此，奥替普拉提供的保护作用可能归因于亲电解毒途径的增强以及AFB1氧化代谢的改变。在使用肝脏线粒体后上清液进行的体外代谢研究中，低剂量奥替普拉预处理促进了AFB1氧化生成黄曲霉毒素P1和Q1，但不生成M1。高剂量（0.1%）奥替普拉预处理增强了AFB1向黄曲霉毒素P1、M1和Q1的初级代谢以及氯仿不溶性代谢物形成。对奥替普拉的一系列1,2 - 二硫醇 - 3 - 硫酮和1,2 - 二硫醇 - 3 - 酮衍生物的喂养研究表明，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）的诱导活性可以通过对1,2 - 二硫醇 - 3 - 硫酮结构的微小修饰轻易分离。未取代的1,2 - 二硫醇 - 3 - 硫酮核强烈诱导亲电解毒酶，但不诱导单加氧酶，并且是体内AFB1与肝脏DNA结合的最有效抑制剂。（摘要截短至400字）
