Kiessling M, Lipinski R, Böhm N, Kleihues P
Carcinogenesis. 1981;2(8):757-61. doi: 10.1093/carcin/2.8.757.
Pretreatment with protein-free diet (PFD) or pregnenolone-16 alpha-carbonitrile (PCN) markedly reduces th toxicity of dimethylnitrosamine (DMN) in rats. PFD causes a shift in DMN metabolism form liver to kidney with a consequent increase in the incidence of kidney tumours. The present study was designed to evaluate the effect of PCN on the carcinogenicity and metabolism of DMN. After pretreatment with PFD, PCN or a combination of both, adult female Wistar rats received a single i.p. dose (60 mg/kg) of DMN. Animals pretreated with PFD and PFD + PCN developed a similar incidence of kidney tumours (83-85%) after a mean survival time of 357 and 396 days, respectively, Animals pretreated with PCN alone had a 50% incidence of renal tumours after a mean survival time of 672 days. This correlates with the initial extent of DMN-induced methylation of kidney DNA. Concentrations of 7-methylguanine and O6-methylguanine were highest and very similar in PFD- and PFD + PCN-pretreated rats, whereas in PCN-conditioned animals the extent of base methylation was 38% lower. Extrarenal tumours, in particular large cystic cholangiomas of the liver, were most frequent in PCN-pretreated rats, probably due to their longer survival time. In contrast to animals pretreated with either PCN or PFD, hepatic DNA methylation was markedly reduced (54-60%) in animals pretreated with both PFD and PCN.
用无蛋白饮食（PFD）或孕烯醇酮 - 16α - 腈（PCN）进行预处理可显著降低大鼠体内二甲基亚硝胺（DMN）的毒性。PFD会使DMN的代谢从肝脏转移至肾脏，从而导致肾肿瘤发病率增加。本研究旨在评估PCN对DMN致癌性和代谢的影响。成年雌性Wistar大鼠在分别用PFD、PCN或两者联合进行预处理后，腹腔注射单次剂量（60 mg/kg）的DMN。经PFD和PFD + PCN预处理的动物，在平均生存时间分别为357天和396天后，肾肿瘤发病率相似（83 - 85%）。单独用PCN预处理的动物，在平均生存时间672天后，肾肿瘤发病率为50%。这与DMN诱导的肾脏DNA甲基化的初始程度相关。在经PFD和PFD + PCN预处理的大鼠中，7 - 甲基鸟嘌呤和O6 - 甲基鸟嘌呤的浓度最高且非常相似，而在经PCN预处理的动物中，碱基甲基化程度低38%。肾外肿瘤，特别是肝脏的大囊性胆管瘤，在经PCN预处理的大鼠中最为常见，这可能是由于它们的生存时间更长。与单独用PCN或PFD预处理的动物不同，经PFD和PCN两者预处理的动物肝脏DNA甲基化显著降低（54 - 60%）。
