MODIFICATION OF AFLATOXIN B-1 BINDING TO DNA INVIVO IN RATS FED PHENOLIC ANTIOXIDANTS, ETHOXYQUIN AND A DITHIOTHIONE
MODIFICATION OF AFLATOXIN B-1 BINDING TO DNA INVIVO IN RATS FED PHENOLIC ANTIOXIDANTS, ETHOXYQUIN AND A DITHIOTHIONE
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DOI：
10.1093/carcin/6.5.759
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发表时间：
1985-01-01
期刊：
影响因子：
4.7
通讯作者：
GROOPMAN, JD
中科院分区：
文献类型：
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作者：
KENSLER, TW;EGNER, PA;GROOPMAN, JD
研究了饮食中3，5-二叔丁基-4-羟基甲苯(BHT)、2(3)-叔丁基-4-羟基苯甲醚(BHA)、乙氧基喹(EQ)和5-(2-吡嗪基)-4-甲基-1，2-二硫醇-3-硫酮(Oltiprz)对大鼠肝肾黄曲霉毒素B1(AFB1)-DNA加合物形成的影响。雄性F344大鼠腹腔注射黄曲霉毒素B_1 1 mg/kg。给药和给药后2小时分离核酸。在黄曲霉毒素1处理前，动物饲喂添加0.5%EQ、0.45%BHT、0.45%BHA或0.1%奥替拉兹的半纯饲料2wk。高效毛细管电泳法分析核酸碱基[高效液相色谱]显示两种组织中都有AFB1代谢物-DNA加合物形成。8，9-二氢-8-(N7-鸟基)-9-羟基黄曲霉毒素B1的主加合物和相关加合物代表apprx。两个组织和所有治疗组中所有加合物的80%-90%。然而，在饮食中加入抗氧化剂导致整体AFB1修饰的DNA水平大幅下降。EQ、BHT、BHA和奥替拉兹使黄曲霉毒素B_1与肝DNA的共价结合降低了91、85、65和76%，与肾DNA的共价结合降低了80、35、62和%。与之相一致的是，所有抗氧化剂都显著提高了对AFB1解毒有重要作用的肝酶、环氧化物水合酶、糖基转移酶和谷胱甘肽转移酶的比活性。除奥替拉兹外，还原型谷胱甘肽水平没有变化，尽管在大多数治疗组中，有助于维持还原型谷胱甘肽池的酶、谷胱甘肽还原酶和G-6-P脱氢酶的活性都升高了。4种抗氧化剂对肝脏谷胱甘肽S转移酶活性的诱导作用与黄曲霉毒素B_1对DNA结合的抑制程度呈极显著正相关(r=0.95)。
The effects of dietary administration of 3,5-di-tert-butyl-4-hydroxytoluene (BHT), 2(3)-tert-butyl-4-hydroxyanisole (BHA), ethoxyquin (EQ) and 5-(2-pyrizinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz) on aflatoxin B1 (AFB1)-DNA adduct formation in vivo in livers and kidneys of rats were investigated. Male F344 rats were treated with 1 mg/kg AFB1 by i.p. administration and nucleic acids isolated 2 h post-dosing. Animals were fed a semipurified diet supplemented with either 0.5% EQ, 0.45% BHT, 0.45% BHA or 0.1% oltipraz for 2 wk prior to AFB1 treatment. Analysis of nucleic acid bases by h.p.l.c. [high performance liquid chromatogaphy] showed that several AFB1 metabolite-DNA adducts were formed in both tissues. The principal and related adducts of 8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 represented .apprx. 80-90% of all adducts in both tissues and in all treatment groups. However, inclusion of the antioxidants in the diet resulted in substantial reductions in overall AFB1 modified DNA levels. EQ, BHT, BHA and oltipraz reduced the covalent binding of AFB1 to liver DNA by 91, 85, 65 and 76% and to kidney DNA by 80, 35, 62 and 64%, respectively. Concordantly, the specific activities of hepatic enzymes of presumed importance to AFB1 detoxification, epoxide hydrase and glycuronyl and glutathione transferases were significantly elevated by all antioxidants. Reduced glutathione levels were unchanged except by oltipraz, although activities of enzymes contributing to the maintenance of reduced glutathione pools, glutathione reductase and G-6-P dehydrogenase were elevated in most treatment groups. An excellent correlation (r = 0.95) was observed between the degree of inhibition of DNA binding by AFB1 and the induction of hepatic glutathione S-transferase activities by the 4 antioxidants.