Chemical and biological properties of indole glucosinolates (glucobrassicins): A review

Induction of phase 2 detoxication enzymes [e.g., glutathione transferases, epoxide hydrolase, NAD(P)H: quinone reductase, and glucuronosyltransferases] is a powerful strategy for achieving protection against carcinogenesis, mutagenesis, and other forms of toxicity of electrophiles and reactive forms of oxygen. Since consumption of large quantities of fruit and vegetables is associated with a striking reduction in the risk of developing a variety of malignancies, it is of interest that a number of edible plants contain substantial quantities of compounds that regulate mammalian enzymes of xenobiotic metabolism. Thus, edible plants belonging to the family Cruciferae and genus Brassica (e.g., broccoli and caulif lower) contain substantial quantities of isothiocyanates (mostly in the form of their glucosinolate precursors) some of which (e.g., sulforaphane or 4-methylsulfinylbutyl isothiocyanate) are very potent inducers of phase 2 enzymes. Unexpectedly, 3-day-old sprouts of cultivars of certain crucifers including broccoli and caulif lower contain 10-100 times higher levels of glucoraphanin (the glucosinolate of sulforaphane) than do the corresponding mature plants. Glucosinolates and isothiocyanates can be efficiently extracted from plants, without hydrolysis of glucosinolates by myrosinase, by homogenization in a mixture of equal volumes of dimethyl sulfoxide, dimethylformamide, and acetonitrile at ؊50°C. Extracts of 3-day-old broccoli sprouts (containing either glucoraphanin or sulforaphane as the principal enzyme inducer) were highly effective in reducing the incidence, multiplicity, and rate of development of mammary tumors in dimethylbenz(a)anthracene-treated rats. Notably, sprouts of many broccoli cultivars contain negligible quantities of indole glucosinolates, which predominate in the mature vegetable and may give rise to degradation products (e.g., indole-3-carbinol) that can enhance tumorigenesis. Hence, small quantities of crucifer sprouts may protect against the risk of cancer as effectively as much larger quantities of mature vegetables of the same variety.

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“…glucobrassicin, neoglucobrassicin (18,25,26), and smaller quantities of 4-hydroxyglucobrassicin (for example, see Fig. 4).…”

Section: Figmentioning

confidence: 99%

Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens

Fahey

Zhang

Talalay

1997

Proc. Natl. Acad. Sci. U.S.A.

1,228

871

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“…ICZ is produced in vivo and in vitro as one of the acid-catalyzed reaction products of non-nutritive indoles such as indole-3-carbinol and glucobrassicin that are present in cabbage and Brussels sprouts and other plants of the Brassica genus (1)(2)(3)(4). ICZ is also produced, presumably from the nutritive indole, tryptophan, as a metabolic product of intestinal bacteria (5).…”

mentioning

confidence: 99%

Regulation of CYP1A1 by Indolo[3,2-b]carbazole in Murine Hepatoma Cells

Chen¹,

Riby²,

Srivastava³

et al. 1995

Journal of Biological Chemistry

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To determine the basis for unexpected differences in CYP1A1 inducing potencies and efficacies for the dietderived indole derivative, indolo[3,2-b]carbazole (ICZ) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), we conducted a systematic analysis of events involved in the induced expression of CYP1A1 in murine hepatoma-derived cell lines (Hepa-1). In contrast to the effects of TCDD, induction kinetics and CYP1A1 mRNA half-life were dependent on ICZ concentration, and the response from low doses of inducer was transient due to rapid clearance of ICZ. TCDD and ICZ produced the same maximum response (i.e. equal efficacies) from a TCDDresponsive CAT reporter construct in Hepa-1 cells. When measured by the immediate responses associated with CYP1A1 expression, including cellular uptake of inducer, receptor transformation and binding to DRE (gel mobility shift assay), initiation of transcription (nuclear run-on assay), and short-term accumulation of mRNA (Northern blot assay), ICZ also exhibited an efficacy equal to that of TCDD and a potency that corresponds to its receptor affinity. ICZ is a potent and selective noncompetitive inhibitor of ethoxyresorufin O-deethylase activity (K i ‫؍‬ 1.5 nM). Taken together these results indicate that ICZ is a bifunctional modulator of CYP1A1 expression with intrinsic efficacy equal to that of TCDD. Indolo[3,2-b]carbazole (ICZ)1 (Structure 1) is a compound of dietary origin present in the gastrointestinal tract of rodents and humans. ICZ is produced in vivo and in vitro as one of the acid-catalyzed reaction products of non-nutritive indoles such as indole-3-carbinol and glucobrassicin that are present in cabbage and Brussels sprouts and other plants of the Brassica genus (1-4). ICZ is also produced, presumably from the nutritive indole, tryptophan, as a metabolic product of intestinal bacteria (5).ICZ is similar in several respects to the potent environmental pollutant, TCDD. Both compounds have immunosuppressive activity in murine fetal thymus organ culture and both substances exhibit potent antiestrogenic activities including inhibition of estrogen-dependent growth of cultured breast tumor cells (6, 7). Additionally, both ICZ and TCDD induce CYP1A1 activity in animals and in cultured cells (1). CYP1A1 is a phase I enzyme involved in the metabolism of many drugs and carcinogens. CYP1A1 is also the enzyme thought to be primarily responsible for the inactivation of estradiol in breast tumor cells (8).Perhaps key to these similarities in activities is the fact that ICZ and TCDD are nearly isosteric and both compounds are potent Ah receptor agonists (9, 10). The Ah receptor is a widely occurring, ligand-activated transcription factor that mediates the activation of CYP1A1, CYP1A2, glutathione S-transferase Ya, and quinone reductase genes. Binding to this receptor is thought also to be responsible for most of the toxic effects of TCDD, including tumor promotion, teratogenesis, and lethal anorexia with wasting, that appear to result mechanistically from effects beyond simple induction of...

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“…1 compound a) is an autolysis product of glucobrassicin (3-indolylmethyl glucosinolate), a compound that occurs naturally in large amounts in a number of vegetables of the Brassica genus (e.g., cabbage, 0.1-1.9 mmol/kg of fresh weight; cauliflower, 0.1-1.6 mmol/kg; and brussels sprouts, 0.5-3.2 mmol/kg) (1)(2)(3). 13C has received considerable attention as a dietary modulator of carcinogenesis (4).…”

mentioning

confidence: 99%

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

Bjeldanes

Kim

Grose

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

515

379

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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.

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Chemical and biological properties of indole glucosinolates (glucobrassicins): A review

Cited by 263 publications

References 56 publications

Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens

Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens

Regulation of CYP1A1 by Indolo[3,2-b]carbazole in Murine Hepatoma Cells

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

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