Musatov S A, Anisimov V N, André V, Vigreux C, Godard T, Sichel F
Department of Medical Biology and Genetics, I.P. Pavlov St. Petersburg State Medical University, Russia.
Cancer Lett. 1999 Apr 26;138(1-2):37-44. doi: 10.1016/s0304-3835(98)00365-6.
The effect of melatonin, an indole hormone of the pineal gland, on the initiation of N-nitroso-N-methylurea (NMU)-induced carcinogenesis in rats and mutagenesis in vitro has been investigated. Two-month-old female LIO rats (groups 1 and 2) were exposed to a single injection of NMU (50 mg/kg of body weight, i.v.). Rats from group 2 were given melatonin orally (20 mg/l) from 18:00 to 09:00 h over 3 days (2 days before and 1 day after NMU injection). Animals from group 1 (control) were administered the solvent (ethanol/water, 1:1000). Rats were followed up to natural death or were sacrificed when moribund. Tumors developed both in rats treated with NMU alone (50.0%) and in rats exposed to NMU plus melatonin (34.8%). The percentage of malignant tumor-bearing rats in group 2 (21.7%) was lower (P < 0.02) than that in the other group (41.7%). Melatonin also decreased the multiplicity of malignant tumors 1.3-fold and reduced the incidence of malignancies in some organs. Two in vitro tests were used for mutagenesis studies: the Ames test (strains TA 100 and TA 102 of Salmonella typhimurium) and the Single Cell Gel Electrophoresis assay (SCGE assay or COMET assay) performed on CHOK1 cells. Melatonin itself revealed no genotoxic effect in either of the tests. No protective action of melatonin (at doses of up to 2 micromol/plate) towards NMU was found in the Ames test. In contrast, in the SCGE assay a slight, but statistically significant (P < 0.001), dose-related anticlastogenic effect of melatonin (10(-10)-10(-7) M) was observed. Thus, our data indicate that melatonin may act as an anti-initiating hormone in NMU-induced carcinogenesis and possess anticlastogenic activity towards NMU in CHOK1 cells.
已对松果体的吲哚类激素褪黑素对N-亚硝基-N-甲基脲（NMU）诱导的大鼠致癌作用起始及体外诱变的影响进行了研究。将2月龄雌性LIO大鼠（第1组和第2组）单次静脉注射NMU（50 mg/kg体重）。第2组大鼠在NMU注射前2天及注射后1天，于18:00至09:00期间口服褪黑素（20 mg/l），持续3天。第1组（对照组）动物给予溶剂（乙醇/水，1:1000）。对大鼠进行随访直至自然死亡，或在濒死时处死。单独用NMU处理的大鼠（50.0%）和暴露于NMU加褪黑素的大鼠（34.8%）均发生了肿瘤。第2组中携带恶性肿瘤的大鼠百分比（21.7%）低于另一组（41.7%）（P < 0.02）。褪黑素还使恶性肿瘤的多发性降低了1.3倍，并降低了某些器官中恶性肿瘤的发生率。采用两种体外试验进行诱变研究：Ames试验（鼠伤寒沙门氏菌TA 100和TA 102菌株）和对CHOK1细胞进行的单细胞凝胶电泳试验（SCGE试验或彗星试验）。褪黑素本身在两种试验中均未显示出遗传毒性作用。在Ames试验中未发现褪黑素（剂量高达2 μmol/平板）对NMU有保护作用。相反，在SCGE试验中，观察到褪黑素（10⁻¹⁰ - 10⁻⁷ M）有轻微但具有统计学意义（P < 0.001）的剂量相关抗断裂作用。因此，我们的数据表明，褪黑素在NMU诱导的致癌作用中可能作为一种抗启动激素，并在CHOK1细胞中对NMU具有抗断裂活性。
