Bailey G S, Loveland P M, Pereira C, Pierce D, Hendricks J D, Groopman J D
Department of Food Science and Technology, Oregon State University, Corvallis 97331.
Mutat Res. 1994 Aug;313(1):25-38. doi: 10.1016/0165-1161(94)90030-2.
Two exposure protocols were used to establish complete dose-response relationships for the hepatic carcinogenicity and DNA adduction in vivo of aflatoxin B1 (AFB1) and aflatoxicol (AFL) in rainbow trout. By passive egg exposure, AFL was taken up less well than AFB1, 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 AFB1. 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 AFB1 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 AFB1 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 AFB1 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 AFB1 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 AFB1 and AFL, we conclude that > 99% of AFL-DNA adducts produced in vivo were identical to those produced by AFB1. 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.
采用两种暴露方案来建立虹鳟鱼体内黄曲霉毒素B1（AFB1）和黄曲霉毒素醇（AFL）的肝脏致癌性及DNA加合物的完整剂量-反应关系。通过被动卵暴露，AFL的摄取效果不如AFB1，但更有效地被隔离到胚胎自身中，从而产生一条与致癌物剂量呈线性关系的胚胎DNA结合曲线，其DNA结合指数比AFB1高3倍。两种黄曲霉毒素产生相同的表型反应，主要是混合性肝细胞/胆管细胞癌。肿瘤反应以logit[发生率]对In[剂量]表示，是平行偏移的非线性反应，在所有检测剂量下，AFL的致癌效力比AFB1高3倍（即产生相同肝脏肿瘤发生率所需的AFB1是AFL的3倍）。通过分子剂量学分析（logit[发生率]对In[DNA加合物]），这两组数据是一致的，表明在总胚胎DNA中体内形成的每个DNA加合物，这两种黄曲霉毒素在肿瘤起始方面同样有效。通过饲料喂养鱼苗暴露，两种致癌物在肝脏中均产生线性DNA结合剂量反应，但通过这种暴露途径，AFL的靶器官DNA结合指数仅为AFB1的1.14倍。肿瘤剂量-反应曲线也未呈现出胚胎暴露所显示的3倍差异，而是紧密相邻的非线性曲线。由于DNA结合指数仅相差14%，因此通过饲料暴露得到的AFL和AFB1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AFB1药代动力学行为的方案依赖性差异，不同的暴露途径基于所施用的剂量产生不同的相对致癌性估计，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。通过与使用AFB1和AFL的二甲基环氧乙烷生成的8,9-环氧化物在体外产生的标准DNA加合物进行比较，我们得出结论，体内产生的AFL-DNA加合物>99%与AFB1产生的相同。因此，在两种母体致癌物对靶器官不表现出不同毒性的所有暴露方案下，应预期会有相似的分子剂量学反应。
