Indoles Derived From Glucobrassicin: Cancer Chemoprevention by Indole-3-Carbinol and 3,3'-Diindolylmethane.

David E. Williams

doi:10.3389/fnut.2021.734334

Abstract

Hydrolysis of glucobrassicin by plant or bacterial myrosinase produces multiple indoles predominantly indole-3-carbinol (I3C). I3C and its major in vivo product, 3,3'-diindolylmethane (DIM), are effective cancer chemopreventive agents in pre-clinical models and show promise in clinical trials. The pharmacokinetics/pharmacodynamics of DIM have been studied in both rodents and humans and urinary DIM is a proposed biomarker of dietary intake of cruciferous vegetables. Recent clinical studies at Oregon State University show surprisingly robust metabolism of DIM in vivo with mono- and di-hydroxylation followed by conjugation with sulfate or glucuronic acid. DIM has multiple mechanisms of action, the most well-characterized is modulation of aryl hydrocarbon receptor (AHR) signaling. In rainbow trout dose-dependent cancer chemoprevention by dietary I3C is achieved when given prior to or concurrent with aflatoxin B1, polycyclic aromatic hydrocarbons, nitrosamines or direct acting carcinogens such as N-methyl-N'-nitro-nitrosoguanidine. Feeding pregnant mice I3C inhibits transplacental carcinogenesis. In humans much of the focus has been on chemoprevention of breast and prostate cancer. Alteration of cytochrome P450-dependent estrogen metabolism is hypothesized to be an important driver of DIM-dependent breast cancer prevention. The few studies done to date comparing glucobrassicin-rich crucifers such as Brussels sprouts with I3C/DIM supplements have shown the greater impact of the latter is due to dose. Daily ingestion of kg quantities of Brussels sprouts is required to produce in vivo levels of DIM achievable by supplementation. In clinical trials these supplement doses have elicited few if any adverse effects. Sulforaphane from glucoraphanin can act synergistically with glucobrassicin-derived DIM and this may lead to opportunities for combinatorial approaches (supplement and food-based) in the clinic.

Highlights

Glucosinolates are found primarily in cruciferous vegetables [1,2,3]
I3C and DIM, the major indoles released upon hydrolysis and ingestion of glucobrassicin from Brussels sprouts and other cruciferous vegetables, have been studied extensively and their beneficial impact on cancer is welldocumented
aryl hydrocarbon receptor (AHR), ER and AR binding are associated with mechanisms ascribed to DIM

Summary

Introduction

Glucosinolates are found primarily in cruciferous vegetables [1,2,3]. This review will focus primarily on the hydrolysis product of glucobrassicin, indole-3-carbinol (I3C), and the major in vivo I3C product, 3,3’-diindolylmethane (DIM). The relevance of many in vitro studies of DIM (typically at concentrations of 10–100 μM) in cancer cells could be questioned as plasma levels following ingestion of supplements have been reported to be ≤1 μM and recent evidence in humans show that a significant portion exists as DIM metabolites with unknown pharmacological activity [20]. The majority of studies above were performed in cell culture and the importance of I3C/DIM regulation of non-coding RNA expression in chemoprevention or therapeutic intervention in human cancer is currently unknown.

Results

Conclusion