METABOLISM, CYTO-TOXICITY, AND GENOTOXICITY OF THE PYRROLIZIDINE ALKALOID SENECIONINE IN PRIMARY CULTURES OF RAT HEPATOCYTES
METABOLISM, CYTO-TOXICITY, AND GENOTOXICITY OF THE PYRROLIZIDINE ALKALOID SENECIONINE IN PRIMARY CULTURES OF RAT HEPATOCYTES
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DOI：
10.1016/0041-008x(91)90221-y
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发表时间：
1981-01-01
影响因子：
3.8
通讯作者：
BYARD, JL
中科院分区：
文献类型：
--
作者：
GREEN, CE;SEGALL, HJ;BYARD, JL
千里光素是一种从千里光中分离的吡咯里西啶生物碱，对成年雄性大鼠肝细胞的原代培养物具有强效毒性。无毒剂量的[14 C]千里光苷（1.9-2.4 nmol/106个细胞）被肝细胞从培养基中迅速吸收，并转化为培养基中回收的极性更强的代谢产物。同时，一些代谢产物与细胞大分子形成稳定的共价键。孵育24小时后，88%的剂量是水溶性的，而只有10%可以用氯仿提取; 1.3%的剂量与三氯乙酸沉淀物质结合，不能用有机溶剂提取。千里光碱是一种强效细胞毒素，表现为乳酸脱氢酶从肝细胞泄漏到周围培养基中以及胶原基质中的细胞损失。在1.6-128 nmol/106个细胞的剂量范围内，获得了细胞毒性的线性剂量-反应关系。共价结合和刺激DNA修复的证据表明，千里光碱具有遗传毒性。刺激DNA修复的最低剂量为16 nmol/106个细胞。基于这些数据，千里光碱不仅是一种有效的肝毒素，而且可能是致癌的。
Senecionine, a pyrrolizidine alkaloid isolated from Senecio vulgaris, was a potent toxicant to primary cultures of adult male rat hepatocytes. A nontoxic dose of [14C]senecionine (1.9-2.4 nmol/106 cells) was rapidly taken up from the culture medium by hepatocytes and converted to more polar metabolites recovered in the culture medium. Concomitantly some metabolites formed stable covalent bonds with cellular macromolecules. After a 24-h incubation, 88% of the dose was water-soluble while only 10% could be extracted with chloroform; 1.3% of the dose was bound to trichloroacetic acid-precipitated material and could not be extracted with organic solvents. Senecionine was a potent cytotoxin as evidenced by a leakage of lactate dehydrogenase from the hepatocytes into the surrounding culture medium and the loss of cells from the collagen substratum. A linear dose-response relationship for cytotoxicity was obtained for doses ranging from 1.6-128 nmol/106 cells. Senecionine was genotoxic as suggested by the evidence of covalent binding and the stimulation of DNA repair. The lowest dose that stimulated DNA repair was 16 nmol/106 cells. Based on these data, senecionine is not only a potent hepatotoxin but is also likely to be carcinogenic.