Navarro Sandi L, Peterson Sabrina, Chen Chu, Makar Karen W, Schwarz Yvonne, King Irena B, Li Shuying S, Li Lin, Kestin Mark, Lampe Johanna W
Bastyr University, Kenmore, WA, USA.
Cancer Prev Res (Phila). 2009 Apr;2(4):345-52. doi: 10.1158/1940-6207.CAPR-08-0178. Epub 2009 Mar 31.
Chemoprevention by isothiocyanates from cruciferous vegetables occurs partly through up-regulation of phase II conjugating enzymes, such as UDP-glucuronosyltransferases (UGT). UGT1A1 glucuronidates bilirubin, estrogens, and several dietary carcinogens. The UGT1A128 polymorphism reduces transcription compared with the wild-type, resulting in decreased enzyme activity. Isothiocyanates are metabolized by glutathione S-transferases (GST); variants may alter isothiocyanate clearance such that response to crucifers may vary by genotype. We evaluated, in a randomized, controlled, crossover feeding trial in humans (n = 70), three test diets (single- and double-"dose" cruciferous and cruciferous plus apiaceous) compared with a fruit and vegetable-free basal diet. We measured serum bilirubin concentrations on days 0, 7, 11, and 14 of each 2-week feeding period to monitor UGT1A1 activity and determined effects of UGT1A128 and GSTM1/GSTT1-null variants on response. Aggregate bilirubin response to all vegetable-containing diets was statistically significantly lower compared with the basal diet (P < 0.03 for all). Within each UGT1A1 genotype, lower bilirubin concentrations were seen in *1/*1 in both single- and double-dose cruciferous diets compared with basal (P < 0.03 for both); *1/*28 in double-dose cruciferous and cruciferous plus apiaceous compared with basal, and cruciferous plus apiaceous compared with single-dose cruciferous (P < 0.02 for all); and *28/28 in all vegetable-containing diets compared with basal (P < 0.02 for all). Evaluation of the effects of diet stratified by GST genotype revealed some statistically significant genotypic differences; however, the magnitude was similar and not statistically significant between genotypes. These results may have implications for altering carcinogen metabolism through dietary intervention, particularly among UGT1A128/*28 individuals.
十字花科蔬菜中的异硫氰酸盐的化学预防作用部分是通过上调Ⅱ相共轭酶（如尿苷二磷酸葡萄糖醛酸基转移酶（UGT））来实现的。UGT1A1可将胆红素、雌激素和几种膳食致癌物进行葡萄糖醛酸化。与野生型相比，UGT1A128多态性会降低转录水平，导致酶活性下降。异硫氰酸盐由谷胱甘肽S-转移酶（GST）代谢；其变体可能会改变异硫氰酸盐的清除率，从而使对十字花科植物的反应因基因型而异。在一项针对人类的随机、对照、交叉喂养试验（n = 70）中，我们评估了三种试验饮食（单剂量和双剂量十字花科蔬菜饮食以及十字花科蔬菜加伞形科蔬菜饮食）与不含水果和蔬菜的基础饮食相比的情况。在每2周喂养期的第0、7、11和14天测量血清胆红素浓度，以监测UGT1A1活性，并确定UGT1A128和GSTM1/GSTT1缺失变体对反应的影响。与基础饮食相比，所有含蔬菜饮食的总胆红素反应在统计学上显著更低（所有P < 0.03）。在每种UGT1A1基因型中，单剂量和双剂量十字花科蔬菜饮食中*1/1基因型的胆红素浓度均低于基础饮食（两者均P < 0.03）；双剂量十字花科蔬菜饮食以及十字花科蔬菜加伞形科蔬菜饮食中1/28基因型的胆红素浓度低于基础饮食，十字花科蔬菜加伞形科蔬菜饮食中该基因型的胆红素浓度低于单剂量十字花科蔬菜饮食（所有P < 0.02）；所有含蔬菜饮食中28/28基因型的胆红素浓度均低于基础饮食（所有P < 0.02）。按GST基因型分层评估饮食的影响发现了一些统计学上显著的基因型差异；然而，各基因型之间的差异幅度相似且无统计学意义。这些结果可能对通过饮食干预改变致癌物代谢具有启示意义，尤其是在UGT1A128/*28个体中。
