Shelton D W, Goeger D E, Hendricks J D, Bailey G S
Carcinogenesis. 1986 Jul;7(7):1065-71. doi: 10.1093/carcin/7.7.1065.
Polychlorinated biphenyls (PCBs) have previously been shown to be inhibitors of carcinogenesis in trout. The mechanism of this inhibition was investigated by studying the effects of PCBs on aflatoxin B1 (AFB1) distribution, metabolism and DNA adduct formation, both in vivo and in vitro. A 24 h distribution study of injected tritiated AFB1 showed more radioactivity in blood, liver and bile in fish fed PCBs, but less in residual carcass. The metabolites of AFB1 found in vivo in blood plasma and liver homogenates were shifted by PCB pretreatment towards greater production of the polar metabolite aflatoxin M1 (AFM1) and glucuronide conjugates. The major metabolite in bile of PCB fish was the glucuronide of aflatoxicol M1 (AFL-M1), which was enhanced 15-fold over controls. Levels of aflatoxicol (AFL) glucuronide, the major conjugate in controls, were unaltered by PCBs. The pattern of AFB1 metabolism in isolated hepatocytes from PCB-prefed fish was consistent with in vivo metabolism. AFB1--DNA adduct formation in a 1 h assay was similar in hepatocytes from PCB-fed and control fish. However, the total rate of AFB1 metabolism was significantly elevated in hepatocytes from PCB-fed fish such that the degree of AFB1--DNA adduct formed per unit AFB1 metabolized was 42% lower than control. Similarly, adduct formation in vivo during the first 24 h post-AFB1 injection in PCB fish was not significantly different from controls. However, over a longer 21 day period, adduct levels in PCB fish were only 48-69% of controls (P less than 0.005, analysis of variance), once peak adduct formation was reached. Thus, initial rates of adduct formation may be misleading in the absence of further information on rates of carcinogen metabolism in vitro and/or pharmacokinetics of peak adduct formation in vivo. These results indicate that PCB inhibition of AFB1 carcinogenesis in trout involves dramatic initial changes in carcinogen distribution, metabolism and elimination which, over time, results in a net reduction of DNA adduct formation.
多氯联苯（PCBs）此前已被证明是鳟鱼致癌作用的抑制剂。通过研究多氯联苯对黄曲霉毒素B1（AFB1）在体内和体外的分布、代谢及DNA加合物形成的影响，对这种抑制作用的机制进行了研究。一项对注射了氚标记AFB1的24小时分布研究表明，喂食多氯联苯的鱼的血液、肝脏和胆汁中的放射性更强，但残留鱼体中的放射性较弱。血浆和肝脏匀浆中体内发现的AFB1代谢产物，经多氯联苯预处理后，向极性代谢产物黄曲霉毒素M1（AFM1）和葡萄糖醛酸结合物的生成量增加的方向转变。多氯联苯处理鱼胆汁中的主要代谢产物是黄曲霉毒素醇M1（AFL-M1）的葡萄糖醛酸结合物，其含量比对照组增加了15倍。对照组中的主要结合物黄曲霉毒素醇（AFL）葡萄糖醛酸结合物的水平未因多氯联苯而改变。来自预先喂食多氯联苯的鱼的分离肝细胞中AFB1的代谢模式与体内代谢一致。在1小时的试验中，喂食多氯联苯的鱼和对照鱼的肝细胞中AFB1-DNA加合物的形成情况相似。然而，喂食多氯联苯的鱼的肝细胞中AFB1的总代谢率显著提高，以至于每代谢单位AFB1形成的AFB1-DNA加合物的程度比对照低42%。同样，在注射AFB1后的最初24小时内，多氯联苯处理鱼体内的加合物形成与对照没有显著差异。然而，在更长的21天期间，一旦达到加合物形成的峰值，多氯联苯处理鱼体内的加合物水平仅为对照的48%-69%（方差分析，P<0.005）。因此，在缺乏关于体外致癌物代谢率和/或体内加合物形成峰值的药代动力学的进一步信息时，加合物形成的初始速率可能会产生误导。这些结果表明，多氯联苯对鳟鱼中AFB1致癌作用的抑制涉及致癌物分布、代谢和消除的显著初始变化，随着时间的推移，导致DNA加合物形成的净减少。
