Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin.

Abstract

Indole-3-carbinol (13C) is a secondary plant metabolite produced in vegetables of the Brassica genus, including cabbage, cauliflower, and brussels sprouts. I3C is both an anti-initiator and a promoter of carcinogenesis. Consumption of 13C by humans and rodents can lead to marked increases in activities ofcytochrome P-450-dependent monooxygenases and in a variety ofphase II drug-metabolizing enzymes. We have reported previously that the enzyme-inducing activity of 13C is mediated through a mechanism requiring exposure of the compound to the low-pH environment of the stomach. We report here the aromatic hydrocarbon responsiveness-receptor Kd values (22 nM-90 nM), determined with C57BL/6J mouse liver cytosol and the in vitro-and in vivo-molar yields (0.1-6%) of the major acid condensation products of 13C. We also show that indolo[3,2-b]carbazole (ICZ) is produced from 13C in yields on the order of 0.01% in vitro and, after oral intubation, in vivo. ICZ has a Kd of 190 pM for aromatic hydrocarbon responsiveness-receptor binding and an EC50 of 269 nM for induction of cytochrome P4501A1, as measured by ethoxyresorufm O-deethylase activity in murine hepatoma Hepa lclc7 cells. The binding affinity of ICZ is only a factor of 3.7 X 10-2 lower than that of the highly toxic environmental contaminant and cancer promoter 2,3,7,8-tetrachlorodibenzo-p-dioxin. ICZ and related condensation products appear responsible for the enzyme-inducing effects of dietary 13C.

Dietary agent indole‐3‐carbinol protects female rats against the hepatotoxicity of the antitumor drug ET‐743 (trabectidin) without compromising efficacy in a rat mammary carcinoma

“…First, DIM, an important metabonate of I3C, which is thought to be at least in part responsible for its chemopreventive efficacy, 24 does not seem to be implicated in the hepatoprotection provided by I3C. This supposition is borne out by the finding that DIM failed to ameliorate any ET-743-induced hepatic changes.…”

“…24 Therefore, we explored whether DIM might be responsible at least in part for the hepatoprotection afforded by I3C. To that end, I3C was replaced with DIM (0.2% in the diet, w/w) and its ability to protect rat livers against the detrimental activity of ET-743 was studied.…”

Expression and inducibility of the human bilirubin UDP-glucuronosyltransferase UGT1A1 in liver and cultured primary hepatocytes: Evidence for both genetic and environmental influences

“…36 While 3-methylcholanthrene obviously has no potential therapeutic utility, less hazardous agents are available that induce hepatic metabolizing enzymes by the same mechanism. 37,38 Furthermore, the risk of adverse effects associated with the long-term use of these agents may be outweighed by the risk of developing life-threatening kernicteric encephalopathy.…”

N-Alkoxy derivatization of indole-3-carbinol increases the efficacy of the G1 cell cycle arrest and of I3C-specific regulation of cell cycle gene transcription and activity in human breast cancer cells

“…Other acid catalyzed products of I3C likely account for the ability of dietary I3C to markedly reduce the incidence of estrogenresponsive mammary tumors in rodents. Several studies have shown that ICZ binds to the aromatic hydrocarbon (Ah) receptor and induces P450 CYP1A1 gene expression, which can alter estrogen metabolism [18,24,25]. However, at least one of the acid catalyzed products, CTr, is a strong estrogen receptor agonist capable of increasing the proliferation rate of cultured human breast cancer cells [22].…”

“…However, at least one of the acid catalyzed products, CTr, is a strong estrogen receptor agonist capable of increasing the proliferation rate of cultured human breast cancer cells [22]. In contrast, I3C has little affinity for either the Ah or estrogen receptors [10,25,26]. Thus, the overall effect of oral I3C may result from a complex balance of the proliferative and anti-proliferative effects of the acid catalyzed products.…”