反式白藜芦醇可以被肠道微生物群分解代谢为二氢白藜芦醇,3,4'-二羟基-反式-二苯乙烯,lunularin,和4-羟基二苄基。这些代谢物可以在结肠中达到相关浓度。然而,并非所有个体都能平等地代谢RSV,因为这取决于他们的RSV肠道微生物群代谢型(即,lunularin生产者vs.非生产者)。然而,这种微生物代谢如何影响二苯乙烯及其微生物代谢产物的癌症化学预防活性尚不清楚。我们研究了膳食二苯乙烯的结构-抗增殖活性关系,它们的肠道微生物代谢产物,以及人类癌症(Caco-2和HT-29)和非致瘤性(CCD18-Co)结肠细胞中的各种类似物。蝶芪的抗增殖IC50值,氧-白藜芦醇,piceatannol,白藜芦醇,二氢白藜芦醇,lunularin,3,4'-二羟基-反式-二苯乙烯,皮诺西尔文,双氢匹诺西尔文,4-羟基-反式-二苯乙烯,4-羟基二苄基,3-羟基二苄基,并计算了4-反式-二苯乙烯乙醇。通过双和多变量分析,IC50值与34个分子特征相关。对CCD18-Co几乎没有或没有观察到活性,而Caco-2比HT-29更敏感,这可以通过它们代谢化合物的不同能力来解释。Caco-2的IC50值范围为11.4±10.1μM(4-羟基-反式-二苯乙烯)至73.9±13.8μM(二氢pinosylvin)。在HT-29中,值的范围为24.4±11.3μM(4-羟基-反式-芪)至96.7±6.7μM(4-羟基二苄基)。在其IC50下,大多数化合物诱导细胞凋亡并将细胞周期阻滞在S期,蝶芪在G2/M,而4-羟基-反式-二苯乙烯和3,4'-二羟基-反式-二苯乙烯在两个阶段都被捕获。较高的Connolly值(较大的尺寸)阻碍了抗增殖活性,而较低的pKa1增强了Caco-2中的活性,而较高的LogP值(更多的疏水性)增加了HT-29中的活性。减少二苯乙烯中的苯乙烯双键是降低抗增殖活性的最关键特征。这些结果(i)表明,肠道微生物群的代谢决定了饮食二苯乙烯的抗增殖作用。因此,RSV消费可能在个体中发挥不同的作用,这取决于他们与RSV代谢相关的肠道微生物群代谢型。(ii)可以帮助设计具有二苯乙烯类和(或)二苄基核心的定制药物来对抗结直肠癌。
trans-Resveratrol can be catabolized by the gut microbiota to dihydroresveratrol, 3,4\'-dihydroxy-trans-stilbene, lunularin, and 4-hydroxydibenzyl. These metabolites can reach relevant concentrations in the colon. However, not all individuals metabolize RSV equally, as it depends on their RSV gut microbiota metabotype (i.e., lunularin producers vs. non-producers). However, how this microbial metabolism affects the cancer chemopreventive activity of stilbenes and their microbial metabolites is poorly known. We investigated the structure-antiproliferative activity relationship of dietary stilbenes, their gut microbial metabolites, and various analogs in human cancer (Caco-2 and HT-29) and non-tumorigenic (CCD18-Co) colon cells. The antiproliferative IC50 values of pterostilbene, oxy-resveratrol, piceatannol, resveratrol, dihydroresveratrol, lunularin, 3,4\'-dihydroxy-trans-stilbene, pinosylvin, dihydropinosylvin, 4-hydroxy-trans-stilbene, 4-hydroxydibenzyl, 3-hydroxydibenzyl, and 4-trans-stilbenemethanol were calculated. IC50 values were correlated with 34 molecular characteristics by bi- and multivariate analysis. Little or no activity on CCD18-Co was observed, while Caco-2 was more sensitive than HT-29, which was explained by their different capacities to metabolize the compounds. Caco-2 IC50 values ranged from 11.4 ± 10.1 μM (4-hydroxy-trans-stilbene) to 73.9 ± 13.8 μM (dihydropinosylvin). In HT-29, the values ranged from 24.4 ± 11.3 μM (4-hydroxy-trans-stilbene) to 96.7 ± 6.7 μM (4-hydroxydibenzyl). At their IC50, most compounds induced apoptosis and arrested the cell cycle at the S phase, pterostilbene at G2/M, while 4-hydroxy-trans-stilbene and 3,4\'-dihydroxy-trans-stilbene arrested at both phases. Higher Connolly values (larger size) hindered the antiproliferative activity, while a lower pKa1 enhanced the activity in Caco-2, and higher LogP values (more hydrophobicity) increased the activity in HT-29. Reducing the styrene double bond in stilbenes was the most critical feature in decreasing the antiproliferative activity. These results (i) suggest that gut microbiota metabolism determines the antiproliferative effects of dietary stilbenes. Therefore, RSV consumption might exert different effects in individuals depending on their gut microbiota metabotypes associated with RSV metabolism, and (ii) could help design customized drugs with a stilbenoid and (or) dibenzyl core against colorectal cancer.