Diwan B A, Henneman J R, Nims R W
Intramural Research Support Program, SAIC Frederick, NCI-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Int J Toxicol. 2001 Mar-Apr;20(2):81-7. doi: 10.1080/10915810151115191.
The effect of the clinically important anticonvulsant phenytoin (DPH) on hepatocarcinogenesis of male F344/NCr rats initiated with a single i.p. dose of N-nitrosodiethylamine (75 mg/kg b.w.) was studied. Beginning 2 weeks post-initiation, the rats received control diet or diet containing 500 or 1,500 ppm DPH or 500 ppm phenobarbital. At 52 weeks age, the incidences (and multiplicities, in units of tumors per tumor-bearing rat) of hepatocellular adenomas were 0%, 17% (1 +/- 0), 42% (1.8 +/- 0.8), or 67% (2.5 +/- 1.9) in rats exposed to N-nitrosodiethylamine alone, or the carcinogen followed by 500 ppm DPH, 1,500 ppm DPH, or 500 ppm phenobarbital, respectively. Between 53 and 79 weeks of age, 39% of rats receiving N-nitrosodiethylamine alone developed multiple (1.5 +/- 0.8) hepatocellular adenomas. A similar incidence (41%) occurred in the rats administered the carcinogen followed by 500 ppm DPH. The incidence of hepatocellular adenomas (88% and 89%) was significantly greater in rats exposed to N-nitrosodiethylamine followed by 1,500 ppm DPH or 500 ppm phenobarbital, respectively. Multiplicities of hepatocellular adenomas were significantly greater than the control value in rats fed 1,500 ppm DPH or 500 ppm phenobarbital (5.9 +/- 4.8 and 10.1 +/- 6.7, respectively), but not in the rats receiving 500 ppm DPH (2.3 +/- 1.6). No rats exposed to N-nitrosodiethylamine alone or the carcinogen followed by 500 ppm DPH developed hepatocellular carcinomas, while hepatocellular carcinomas occurred in 29% or 67% of the rats given 1,500 ppm DPH or 500 ppm phenobarbital, respectively, following initiation. Increases in hepatic CYP2B-mediated benzyloxyresorufin O-dealkylation activity in rats exposed to 500 and 1,500 ppm DPH for 2 or 23 weeks were approximately 50% and approximately 100%, respectively, of the maximal induction caused by 500 ppm phenobarbital. Thus, in the rat model, DPH enhanced N-nitrosodiethyl-amine-initiated hepatocarcinogenesis when administered at a dose causing maximal CYP2B induction.
研究了具有临床重要意义的抗惊厥药物苯妥英（DPH）对经腹腔注射单次剂量N-亚硝基二乙胺（75mg/kg体重）引发肝癌的雄性F344/NCr大鼠的影响。在引发后2周开始，大鼠接受对照饮食或含500或1500ppm DPH或500ppm苯巴比妥的饮食。在52周龄时，单独暴露于N-亚硝基二乙胺的大鼠肝细胞腺瘤的发生率（以及每只荷瘤大鼠的肿瘤数量）为0%，而暴露于致癌物后再给予500ppm DPH、1500ppm DPH或500ppm苯巴比妥的大鼠肝细胞腺瘤的发生率分别为17%（1±0）、42%（1.8±0.8）或67%（2.5±1.9）。在53至79周龄之间，单独接受N-亚硝基二乙胺的大鼠中有39%发生了多个（1.5±0.8）肝细胞腺瘤。在给予致癌物后再给予500ppm DPH的大鼠中也出现了类似的发生率（41%）。分别暴露于N-亚硝基二乙胺后再给予1500ppm DPH或500ppm苯巴比妥的大鼠肝细胞腺瘤的发生率（88%和89%）显著更高。给予1500ppm DPH或500ppm苯巴比妥的大鼠肝细胞腺瘤的数量显著高于对照组（分别为5.9±4.8和10.1±6.7），但给予500ppm DPH的大鼠（2.3±1.6）则没有。单独暴露于N-亚硝基二乙胺或暴露于致癌物后再给予500ppm DPH的大鼠均未发生肝细胞癌，而在引发后分别给予1500ppm DPH或500ppm苯巴比妥的大鼠中，肝细胞癌的发生率分别为29%或67%。暴露于500和1500ppm DPH达2周或23周的大鼠肝脏中CYP2B介导的苄氧基试卤灵O-脱烷基化活性的增加分别约为500ppm苯巴比妥引起的最大诱导作用的50%和约100%。因此，在大鼠模型中，当以引起最大CYP2B诱导的剂量给药时，DPH增强了N-亚硝基二乙胺引发的肝癌发生。
