Ghia M, Robbiano L, Allavena A, Martelli A, Brambilla G
Institute of Pharmacology, University of Genoa, Italy.
Toxicol Appl Pharmacol. 1993 May;120(1):120-5. doi: 10.1006/taap.1993.1094.
The genotoxic activity of 1,3-dichloropropene, which has been classified as possibly carcinogenic to humans, was investigated in rats given high single doses of this chloroolefin. A dose-related amount of DNA fragmentation was observed at doses ranging from 62.5 to 250 mg/kg in liver and gastric mucosa, both of which are targets of DCP carcinogenic activity, as well as in the kidney. The frequency of DNA breaks, that were to a large extent repaired within 24 hr, was higher after po than after ip administration in the liver, while the converse occurred in the kidney. Any evidence of DNA fragmentation was, in contrast, absent in lung, bone marrow, and brain which are not sites of DCP-induced tumor development. A role of cytochrome P450 in the activation of DCP is suggested by the lower degree of liver DNA fragmentation observed in rats pretreated with methoxsalen. DCP produced a dose-dependent reduction of the liver GSH level, an effect that presumably hinders its detoxification and thus favors its DNA-damaging activity. In contrast with the satisfactory prediction of DCP carcinogenic activity provided by the results of the in vivo DNA damage/alkaline elution assay, neither the in vivo rat hepatocyte DNA repair assay nor the micronucleus assay, carried out on bone marrow, spleen, and liver cells of partially hepatectomized rats, supplied any evidence of DCP genotoxicity.
1,3 - 二氯丙烯已被归类为对人类可能致癌，对给予高单次剂量该氯代烯烃的大鼠的遗传毒性活性进行了研究。在肝脏、胃黏膜（这两者都是二氯丙烯致癌活性的靶器官）以及肾脏中，在62.5至250毫克/千克的剂量范围内观察到了与剂量相关的DNA片段化。DNA断裂的频率在很大程度上在24小时内得到修复，经口给药后肝脏中的频率高于腹腔注射后，而在肾脏中情况则相反。相比之下，在肺、骨髓和大脑中未发现任何DNA片段化的迹象，这些部位不是二氯丙烯诱导肿瘤发生的部位。用甲氧沙林预处理的大鼠肝脏中观察到的DNA片段化程度较低，这表明细胞色素P450在二氯丙烯的活化中起作用。二氯丙烯使肝脏谷胱甘肽水平呈剂量依赖性降低，这种作用可能会阻碍其解毒，从而有利于其DNA损伤活性。与体内DNA损伤/碱性洗脱试验结果对二氯丙烯致癌活性的良好预测相反，在部分肝切除大鼠的骨髓、脾脏和肝脏细胞上进行的体内大鼠肝细胞DNA修复试验和微核试验均未提供二氯丙烯遗传毒性的任何证据。
