Ludeke B I, Dominé F, Ohgaki H, Kleihues P
Department of Pathology, University of Zürich, Switzerland.
Carcinogenesis. 1992 Dec;13(12):2467-70. doi: 10.1093/carcin/13.12.2467.
Diallyl sulfide (DAS), a major component of garlic oil, is an inhibitor of tumorigenesis by various metabolically activated carcinogens. In rats, pretreatment with DAS has been observed to suppress completely the induction of oesophageal neoplasms by N-nitrosomethylbenzylamine (NMBzA) (Wargovich et al. (1988) Cancer Res., 48, 6872-6875). This communication reports the effects of DAS on overall NMBzA metabolism and on DNA methylation of NMBzA in vivo under conditions equivalent to a single treatment of the chemoprevention assay. Male Fischer 344 rats received a single i.g. dose of DAS (200 mg/kg body wt) followed by an s.c. injection of [methyl-14C]NMBzA (3.5 mg/kg). In controls, exhalation of 14CO2 was complete within 5 h (t1/2max = 1.2 h), with 50% of the injected radioactivity recovered as 14CO2. When DAS was given 3 h prior to [methyl-14C]NMBzA, 49% of the injected radioactivity was released within 10 h (t1/2max = 3 h). When DAS was administered 18 h before the carcinogen, 42% of [methyl-14C]NMBzA was converted to 14CO2, with exhalation complete after 6 h (t1/2max = 1.8 h). We further examined the effects of acute doses of 10-200 mg/kg of DAS on DNA methylation by a single dose of NMBzA (3.5 mg/kg; survival time, 6 h) administered 3 h later. At 200 mg/kg, DAS inhibited the formation of O6-methyldeoxyguanosine (O6-MEdG) in oesophagus (-26%), nasal mucosa (-51%), trachea (-68%) and lung (-78%). In liver, levels of 7-MEdG were reduced by 43%. Decreases in DNA methylation were proportional to dose for > 25 mg/kg of DAS in oesophagus, liver and nasal mucosa, for 25-200 mg/kg in trachea and 10-50 mg/kg in lung. The dose-activity relationship for inhibition by DAS of DNA methylation by NMBzA suggests that short-term modulation of carcinogen bioactivation in situ contributes to but may not be sufficient for the chemo-prevention of nitrosamine tumorigenesis by DAS.
二烯丙基硫醚（DAS）是大蒜油的主要成分，是多种经代谢活化的致癌物诱发肿瘤的抑制剂。在大鼠中，已观察到用DAS预处理可完全抑制N-亚硝基甲基苄胺（NMBzA）诱导的食管肿瘤（Wargovich等人，（1988年）《癌症研究》，48，6872 - 6875）。本通讯报道了在与化学预防试验单次治疗相当的条件下，DAS对体内NMBzA整体代谢及NMBzA DNA甲基化的影响。雄性Fischer 344大鼠经口给予单次剂量的DAS（200 mg/kg体重），随后皮下注射[甲基 - 14C]NMBzA（3.5 mg/kg）。在对照组中，14CO2在5小时内呼出完全（t1/2max = 1.2小时），注射放射性的50%以14CO2形式回收。当在[甲基 - 14C]NMBzA前3小时给予DAS时，10小时内注射放射性的49%被释放（t1/2max = 3小时）。当在致癌物前18小时给予DAS时，42%的[甲基 - 14C]NMBzA转化为14CO2，6小时后呼出完全（t1/2max = 1.8小时）。我们进一步研究了急性剂量10 - 200 mg/kg的DAS对3小时后给予的单次剂量NMBzA（3.5 mg/kg；存活时间6小时）引起的DNA甲基化的影响。在200 mg/kg时，DAS抑制食管（-26%）、鼻粘膜（-51%）、气管（-68%）和肺（-78%）中O6 - 甲基脱氧鸟苷（O6 - MEdG）的形成。在肝脏中，7 - MEdG水平降低了43%。在食管、肝脏和鼻粘膜中，当DAS剂量> 25 mg/kg时，DNA甲基化的降低与剂量成比例；在气管中为25 - 200 mg/kg，在肺中为10 - 50 mg/kg。DAS对NMBzA引起的DNA甲基化抑制的剂量 - 活性关系表明，原位短期调节致癌物生物活化有助于但可能不足以通过DAS对亚硝胺肿瘤发生进行化学预防。
