He Y H, Friesen M D, Ruch R J, Schut H A
Department of Pathology, Medical College of Ohio, Toledo, OH 43614-5806, USA.
Food Chem Toxicol. 2000 Jan;38(1):15-23. doi: 10.1016/s0278-6915(99)00117-9.
The chemopreventive properties of dietary indole-3-carbinol (I3C) were evaluated by assessing its effect on DNA adduct formation and metabolism of the dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and the induction of cytochromes P450 1A1 and -1A2 in female F344 rats. In experiment 1, animals on I3C diets (0, 0.02% or 0.1%, w/w) were treated by gavage with 1mg/kg/day of PhIP for 23 days. On days 2, 9, 16 and 23, their 24-hr urine was collected and unmetabolized PhIP was measured by GC/MS. On day 24, the animals were sacrificed, and DNA from pancreas, spleen, white blood cells (WBCs), lung, colon, kidney, mammary epithelial cells, caecum, heart, small intestine, liver and stomach was isolated for determination of PhIP-DNA adduct levels by (32)P-postlabelling assays. Except in the mammary gland, I3C diets significantly inhibited PhIP-DNA adduct formation in WBCs and in all organs, ranging from 34.7 to 67.7% with the 0.02% I3C diet to 68.4 to 95.3% with the 0.1% I3C diet. I3C diets also significantly decreased the concentration of urinary unmetabolized PhIP to 29.5-38.4% (0.02% I3C) and 12.8-17.8% (0.1% I3C) of values obtained with the I3C-free diet. In experiment 2, animals were either treated by intubation of I3C at 100 or 200mg/kg for 2 consecutive days or given an I3C-containing diet (0.02% or 0.1%, w/w) for 2 weeks. The expression and activity of cytochromes P450 1A1 and -1A2 were studied by Northern blots, Western blots, and in vitro enzyme determinations. Both the expression and activity of these cytochromes were induced by all of the I3C treatments. It is concluded that, in the female F344 rat, dietary I3C inhibits PhIP-DNA adduct formation and accelerates PhIP metabolism, probably through induction of cytochromes P450 1A1 and -1A2. The chemopreventive properties of I3C in PhIP-induced carcinogenesis are probably mediated through enhancement of PhIP detoxification pathways.
通过评估膳食吲哚 - 3 - 甲醇（I3C）对DNA加合物形成以及膳食致癌物2 - 氨基 - 1 - 甲基 - 6 - 苯基咪唑并[4,5 - b]吡啶（PhIP）代谢的影响，以及对雌性F344大鼠细胞色素P450 1A1和 - 1A2的诱导作用，来评价I3C的化学预防特性。在实验1中，给予I3C饮食（0、0.02%或0.1%，w/w）的动物通过灌胃给予1mg/kg/天的PhIP，持续23天。在第2、9、16和23天，收集它们24小时的尿液，并用气相色谱/质谱法测量未代谢的PhIP。在第24天，处死动物，分离胰腺、脾脏、白细胞（WBC）、肺、结肠、肾脏、乳腺上皮细胞、盲肠、心脏、小肠、肝脏和胃的DNA，通过（32）P后标记分析法测定PhIP - DNA加合物水平。除乳腺外，I3C饮食显著抑制了白细胞和所有器官中PhIP - DNA加合物的形成，0.02% I3C饮食组的抑制率为34.7%至67.7%，0.1% I3C饮食组的抑制率为68.4%至95.3%。I3C饮食还显著降低了尿中未代谢PhIP的浓度，降至无I3C饮食组所得值的29.5 - 38.4%（0.02% I3C）和12.8 - 17.8%（0.1% I3C）。在实验2中，动物连续2天通过插管给予100或200mg/kg的I3C，或给予含I3C的饮食（0.02%或0.1%，w/w），持续2周。通过Northern印迹法、Western印迹法和体外酶活性测定法研究细胞色素P450 1A1和 - 1A2的表达和活性。所有I3C处理均诱导了这些细胞色素的表达和活性。得出的结论是，在雌性F344大鼠中，膳食I3C抑制PhIP - DNA加合物的形成并加速PhIP代谢，可能是通过诱导细胞色素P450 1A1和 - 1A2。I3C在PhIP诱导的致癌过程中的化学预防特性可能是通过增强PhIP解毒途径介导的。
