QUANTITATIVE CARCINOGENESIS AND DOSIMETRY IN RAINBOW-TROUT FOR AFLATOXIN-B-1 AND AFLATOXICOL, 2 AFLATOXINS THAT FORM THE SAME DNA ADDUCT
QUANTITATIVE CARCINOGENESIS AND DOSIMETRY IN RAINBOW-TROUT FOR AFLATOXIN-B-1 AND AFLATOXICOL, 2 AFLATOXINS THAT FORM THE SAME DNA ADDUCT
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DOI：
10.1016/0165-1161(94)90030-2
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发表时间：
1994-08-01
期刊：
影响因子：
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通讯作者：
GROOPMAN, JD
中科院分区：
文献类型：
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作者：
BAILEY, GS;LOVELAND, PM;GROOPMAN, JD
采用两种暴露方案建立了黄曲霉毒素B-1 （AFB(1)）和黄曲霉毒素（AFL）在虹鳟鱼体内的肝脏致癌性和DNA内聚的完全剂量-反应关系。通过被动的卵子暴露，AFL的吸收不如AFB(1)，但更有效地隔离在胚胎本身，从而产生与致癌物剂量成线性关系的胚胎DNA结合曲线，其DNA结合指数是AFB的三倍(1)。两种黄曲霉毒素产生相同的表型反应，主要是混合肝细胞/胆管细胞癌。肿瘤反应（logit[发生率]vs. In[剂量]）是平行抵消的，非线性反应显示，在所有检测剂量下，AFL的致癌效力要高出三倍（即AFB比产生同等肝脏肿瘤发病率所需的AFL多3倍）。通过分子剂量分析（logit[发生率]vs. In [DNA加合物]），两个数据集是一致的，这表明，在体内总胚胎DNA中形成的每一个DNA加合物，这两种黄曲霉毒素在肿瘤发生中的效率是一样的。通过膳食炸鱼暴露，两种致癌物均在肝脏中产生线性DNA结合剂量反应，但通过该暴露途径，AFL靶器官DNA结合指数仅为AFB的1.14倍(1)。肿瘤剂量-反应曲线也没有表现出胚胎暴露所显示的三倍差异，而是紧密定位的非线性曲线。由于DNA结合指数仅相差14%，因此饮食暴露对AFL和AFB(1)的分子剂量学曲线与肿瘤反应曲线相似。这些结果表明，由于AFL和AFB(1)药代动力学行为的方案依赖差异，不同的暴露途径产生了基于应用剂量的不同相对致癌性估计，但基于所接受的分子剂量的效力比较对于两种方案是相似的。通过与AFB(1)和AFL的二甲基氯烷生成的8,9-环氧化物在体外生成的标准DNA加合物进行比较，我们得出的结论是，体内生成的AFL-DNA加合物中有50%与AFB产生的加合物相同。因此，在两种母体致癌物对靶器官没有表现出不同毒性的所有暴露方案下，应该期望类似的分子剂量学反应。
Two exposure protocols were used to establish complete dose-response relationships for the hepatic carcinogenicity and DNA adduction in vivo of aflatoxin B-1 (AFB(1)) and aflatoxicol (AFL) in rainbow trout. By passive egg exposure, AFL was taken up less well than AFB(1), but was more efficiently sequestered into the embryo itself, to produce an embryonic DNA binding curve that was linear with carcinogen dose and with a DNA binding index three-fold greater than AFB(1). Both aflatoxins produced the same phenotypic response, predominantly mixed hepatocellular/cholangiocellular carcinoma. Tumor responses as logit [incidence] vs. In [dose] were parallel-offset, non-linear responses showing a three-fold greater carcinogenic potency for AFL at all doses examined (i.e. 3 times more AFB, than AFL required to produce an equivalent liver tumor incidence). By molecular dosimetry analysis (logit [incidence] vs. In [DNA adducts]), the two data sets were coincident, indicating that, per DNA adduct formed in vivo in total embryonic DNA, these two aflatoxins were equally efficient in tumor initiation. By dietary fry exposure, both carcinogens produced linear DNA binding dose responses in liver, but with an AFL target organ DNA binding index only 1.14 times that of AFB(1) by this exposure route. The tumor dose-response curves also did not exhibit the three-fold difference shown by embryo exposure, but were closely positioned non-linear curves. Since the DNA binding indices differed by only 14%, the resulting molecular dosimetry curves for AFL and AFB(1) by dietary exposure were similar to the tumor response curves. These results indicate that differing exposure routes produced differing relative carcinogenicity estimates based on doses applied, as a result of protocol-dependent differences in AFL and AFB(1) pharmacokinetic behaviors, but that potency comparisons based on molecular dose received were similar for the two protocols. By comparison with standard DNA adducts produced in vitro using the dimethyloxirane-produced 8,9-epoxides of AFB(1) and AFL, we conclude that > 99% of AFL-DNA adducts produced in vivo were identical to those produced by AFB,. Thus similar molecular dosimetry responses should be expected under all exposure protocols in which the two parent carcinogens do not exhibit differing toxicities to the target organ.