Martelli A, Mereto E, Ghia M, Orsi P, Allavena A, De Pascalis C R, Brambilla G
Department of Internal Medicine, Division of Clinical Pharmacology and Toxicology, University of Genoa, I-16132, Genoa, Italy.
Mutat Res. 1998 Nov 9;419(1-3):33-41. doi: 10.1016/s1383-5718(98)00122-3.
Progesterone (PG) and three structurally similar synthetic progestins-norethisterone (NE), allylestrenol (AE), and dydrogesterone (DG)-have been compared for their ability to induce the formation of micronuclei and of enzyme-altered foci in the liver of female rats. In the micronucleus assay, carried out in rats given a single p.o. dose of 100 mg kg-1 3 days before partial hepatectomy and sacrificed for cell sampling 2 days later, the frequency of micronucleated hepatocytes was 3.5-fold higher than in controls with PG, 2.8-fold with DG, 2.2-fold with NE and 2.1-fold with AE, but the increase was statistically significant only for PG. In the liver foci assay, performed to evaluate the tumor initiating activity of p. o. dosing with 100 mg kg-1 once a week for 6 successive weeks, the values of the number and area of gamma-glutamyltranspeptidase-positive foci were, as compared to controls, 15.9- and 100-fold higher with NE, and 13.9- and 52-fold higher with AE, but only the increase of area produced by NE was statistically significant; PG and DG did not display in this test any activities. Considered together with previous findings, these results suggest that NE might be biotransformed in the liver into reactive species and thus behave as a weak genotoxic agent.
已对孕酮（PG）以及三种结构相似的合成孕激素——炔诺酮（NE）、烯丙雌醇（AE）和地屈孕酮（DG）诱导雌性大鼠肝脏中微核形成和酶改变灶形成的能力进行了比较。在微核试验中，于大鼠部分肝切除术前3天经口给予单次剂量100 mg/kg，并于2天后处死以进行细胞取样，微核化肝细胞的频率比对照组高3.5倍（PG组）、2.8倍（DG组）、2.2倍（NE组）和2.1倍（AE组），但仅PG组的增加具有统计学意义。在肝脏灶试验中，为评估每周经口给予100 mg/kg连续6周的肿瘤启动活性而进行，与对照组相比，γ-谷氨酰转肽酶阳性灶的数量和面积值在NE组分别高15.9倍和100倍，在AE组分别高13.9倍和52倍，但仅NE组产生的面积增加具有统计学意义；PG和DG在该试验中未显示任何活性。结合先前的研究结果，这些结果表明NE可能在肝脏中生物转化为反应性物质，因此表现为一种弱基因毒性剂。
