Hepatocarcinogenicity of hexachlorobenzene in rats and the sex difference in hepatic iron status and development of porphyria.
Hepatocarcinogenicity of hexachlorobenzene in rats and the sex difference in hepatic iron status and development of porphyria.
复制标题
六氯苯对大鼠的肝癌致癌性以及肝铁状态和卟啉症发生的性别差异。
DOI：
10.1093/carcin/6.4.631
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发表时间：
1985
期刊：
影响因子：
4.7
通讯作者：
J. Cabral
中科院分区：
文献类型：
--
作者：
A. Smith;J. Francis;D. Dinsdale;M. Manson;J. Cabral
六氯苯（HCB）以0.02%的浓度饲喂F344大鼠，连续15周。由于尿卟啉原脱羧酶活性的降低，雌性出现了大量的卟啉症，而雄性则没有。尽管对照组女性的肝脏非血红素铁水平是男性的3-5倍（铁与这种疾病的发病机制有关），但对男性进行铁预负荷并没有增加其易感性。经过90周的HCB治疗后，100%存活的女性患有多发性肝肿瘤，这些肿瘤呈强烈的γ -谷氨酰转肽酶（GGT）阳性，组织学分类为肿瘤结节或肝细胞癌。相比之下，只有16%的男性患了比女性更小、每个肝脏数量更少的肿瘤。尽管在处理过的男女肝脏中均未检测到尿卟啉原脱羧酶活性，但男性的卟啉积累仍明显少于女性。在肿瘤和周围组织之间没有发现卟啉水平或酶活性的差异，表明肿瘤没有恢复到非卟啉状态。肿瘤反应的性别差异不能用肝脏HCB浓度的差异来解释。在HCB治疗90周后，男性和女性的肝脏非血红素铁浓度下降，肿瘤中的浓度甚至更低。这些研究表明，雌性大鼠不仅对HCB的卟啉生成作用远比雄性大鼠敏感，而且对肝癌的致癌作用也远比雄性大鼠敏感，这表明这两种毒性表现之间的联系可能也适用于其他多卤芳烃。
Hexachlorobenzene (HCB) was fed to male and female F344 rats as 0.02% of the diet for 15 weeks. Females developed a massive porphyria, due to depression of uroporphyrinogen decarboxylase activity, whereas males did not. Although hepatic non-haem iron levels in control females were 3-5 times greater than males (iron is implicated in the pathogenesis of this condition) preloading the latter with iron did not increase their susceptibility. After 90 weeks of HCB treatment 100% of surviving females had multiple liver tumours which were strongly gamma-glutamyl transpeptidase (GGT) positive and histologically classified as neoplastic nodules or hepatocellular carcinomas. In contrast, only 16% of males developed tumours which were smaller and fewer in number per liver than those in females. Accumulation of porphyrins was still significantly less in males than females although no uroporphyrinogen decarboxylase activity was detected in treated livers of either sex. No differences in porphyrin levels or enzyme activity were found between tumours and surrounding tissue showing that tumours did not revert to a non-porphyric state. The sex difference in tumour response could not be explained by differences in hepatic HCB concentrations. Non-haem iron concentrations of livers fell after HCB treatment for 90 weeks in both sexes and were even lower in tumours. These studies demonstrate that not only are female rats far more sensitive than males to the porphyrinogenic effects of HCB but also to the hepatocarcinogenic actions, suggesting a link between these two manifestations of toxicity that may also apply to other polyhalogenated aromatics.