Post-ingestion conversion of dietary indoles into anticancer agents |
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Authors: | Li Ping Lin Dan Liu Jia Cheng Qian Liang Wu Quan Zhao Ren Xiang Tan |
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Institution: | State Key Laboratory of Pharmaceutical Biotechnology, Institute of Functional Biomolecules, Nanjing University, Nanjing 210023, China;State Key Laboratory Cultivation Base for TCM Quality and Efficacy, Nanjing University of Chinese Medicine, Nanjing 210023, China |
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Abstract: | There are health benefits from consuming cruciferous vegetables that release indole-3-carbinol (I3C), but the in vivo transformation of I3C-related indoles remains underinvestigated. Here we detail the post-ingestion conversion of I3C into antitumor agents, 2-(indol-3-ylmethyl)-3,3′-diindolylmethane (LTr1) and 3,3′-diindolylmethane (DIM), by conceptualizing and materializing the reaction flux derailing (RFD) approach as a means of unraveling these stepwise transformations to be non-enzymatic but pH-dependent and gut microbe-sensitive. In the upper (or acidic) gastrointestinal tract, LTr1 is generated through Michael addition of 3-methyleneindolium (3MI, derived in situ from I3C) to DIM produced from I3C via the formaldehyde-releasing (major) and CO2-liberating (minor) pathways. In the large intestine, ‘endogenous’ I3C and DIM can form, respectively, from couplings of formaldehyde with one and two molecules of indole (a tryptophan catabolite). Acid-producing gut bacteria such as Lactobacillus acidophilus facilitate the H+-promotable steps. This work updates our understanding of the merits of I3C consumption and identifies LTr1 as a drug candidate. |
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Keywords: | indole-3-carbinol reaction flux derailing (RFD) approach 2-(indol-3-ylmethyl)-3 3′ -diindolylmethane (LTr1) anticancer Lactobacillus acidophilus |
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