Heinonen J T, Fisher R, Brendel K, Eaton D L
Department of Environmental Health, University of Washington, Seattle 98195, USA.
Toxicol Appl Pharmacol. 1996 Jan;136(1):1-7. doi: 10.1006/taap.1996.0001.
Although epidemiological studies suggest that aflatoxin B1 (AFB1) is a human carcinogen, at least in the presence of hepatitis B virus infection, animal studies have demonstrated large differences in species sensitivity to AFB1, and the sensitivity of humans relative to experimental animals remains unclear. The purpose of this study was to determine the profile of AFB1 metabolism and the extent of AFB1 binding to cell macromolecules in human liver slices under experimental conditions that would allow direct comparison to similar endpoints in the rat, a species sensitive to the carcinogenic actions of AFB1. Liver slices were prepared from three individual human liver samples with a Krumdieck tissue slicer and incubated with 0.5 microM [3H]AFB1 for 2 hr. Significant interindividual variations were observed in the rates of oxidative metabolite formation and in specific binding to cell macromolecules. The rates of oxidative metabolism of AFB1 to AFQ1, AFP1, and AFM1 in the three human liver samples were similar to those previously observed in rat liver slices. AFB1-GSH conjugate formation was not detected in any of the human liver samples, and yet specific binding of AFB1 to cell macromolecules was considerably lower in the human liver slices relative to that in rat liver slices. AFB1-DNA binding levels ranged from 3 to 26% of control rat and AFB1-RNA binding levels ranged from 25 to 49% of control rat. The AFB1-protein binding level in the one human sample measured was 20% of that observed for control rat. While these results suggest that humans do not form as much AFBO as the rat, they are also consistent with the hypothesis that humans do not possess GST isozyme(s) with high specific activity toward AFBO. Significant individual differences in AFB1 metabolism and binding between humans suggest the presence of genetic and/or environmental factors that may confer large variability in susceptibility to AFB1.
尽管流行病学研究表明黄曲霉毒素B1（AFB1）是一种人类致癌物，至少在存在乙型肝炎病毒感染的情况下是如此，但动物研究显示不同物种对AFB1的敏感性存在很大差异，而人类相对于实验动物的敏感性仍不清楚。本研究的目的是在能够直接与对AFB1致癌作用敏感的大鼠的类似终点进行比较的实验条件下，确定人肝切片中AFB1的代谢概况以及AFB1与细胞大分子的结合程度。用Krumdieck组织切片机从三个个体的人肝样本制备肝切片，并与0.5微摩尔[3H]AFB1孵育2小时。在氧化代谢产物形成速率和与细胞大分子的特异性结合方面观察到显著的个体间差异。三个人肝样本中AFB1氧化代谢为AFQ1、AFP1和AFM1的速率与先前在大鼠肝切片中观察到的速率相似。在任何一个人肝样本中均未检测到AFB1 - GSH缀合物的形成，然而相对于大鼠肝切片，人肝切片中AFB1与细胞大分子的特异性结合显著较低。AFB1 - DNA结合水平为对照大鼠的3%至26%，AFB1 - RNA结合水平为对照大鼠的25%至49%。所检测的一个人样本中AFB1 - 蛋白质结合水平为对照大鼠的20%。虽然这些结果表明人类形成的AFBO不如大鼠多，但它们也与人类不具有对AFBO具有高比活性的谷胱甘肽S - 转移酶同工酶这一假设一致。人类之间AFB1代谢和结合的显著个体差异表明存在可能导致对AFB1易感性差异很大的遗传和/或环境因素。
