Induction of phase 2 antioxidant enzymes by broccoli sulforaphane: perspectives in maintaining the antioxidant activity of vitamins a, C, and e

Abstract

Consumption of fruits and vegetables is recognized as an important part of a healthy diet. Increased consumption of cruciferous vegetables in particular has been associated with a decreased risk of several degenerative and chronic diseases, including cardiovascular disease and certain cancers. Members of the cruciferous vegetable family, which includes broccoli, Brussels sprouts, cauliflower, and cabbage, accumulate significant concentrations of glucosinolates, which are metabolized in vivo to biologically active isothiocyanates (ITCs). The ITC sulforaphane, which is derived from glucoraphanin, has garnered particular interest as an indirect antioxidant due to its extraordinary ability to induce expression of several enzymes via the KEAP1/Nrf2/ARE pathway. Nrf2/ARE gene products are typically characterized as Phase II detoxification enzymes and/or antioxidant (AO) enzymes. Over the last decade, human clinical studies have begun to provide in vivo evidence of both Phase II and AO enzyme induction by SF. Many AO enzymes are redox cycling enzymes that maintain redox homeostasis and activity of free radical scavengers such as vitamins A, C, and E. In this review, we present the existing evidence for induction of PII and AO enzymes by SF, the interactions of SF-induced AO enzymes and proposed maintenance of the essential vitamins A, C, and E, and, finally, the current view of genotypic effects on ITC metabolism and AO enzyme induction and function.

Keywords: antioxidant enzymes; broccoli sulforaphane; phase II enzymes; vitamins ACE.

Figure 1

Hydrolysis of glucoraphanin by myrosinase or gut microorganisms to the biologically active ITC sulforaphane. Glucoraphanin (GR) or 4-methylsulfinylbutyl glucosinolate is the major glucosinolate found within broccoli. Upon physical damage to the plant, the enzyme myrosinase, which is segregated from GR, is released and catalyzes the hydrolysis of GR to the isothiocyanate sulforaphane (SF). Additionally, microorganisms within the human gut can catalyze hydrolysis of GR to SF. Contribution of gut microorganism catalysis is important in SF production due to inactivation of myrosinase by common culinary preparation of broccoli via heating, which inactivates myrosinase.

Figure 2

Mechanism of ARE-mediated detoxifying and antioxidant enzyme induction by sulforaphane. (A) Under basal conditions, the transcription factor NRF2 is sequestered within the cytosol by the repressor proteins Keap1 and cullin 3 (CUL3), presenting it for proteosomal degradation via ubiquitination. Sulforaphane, through modification of the highly redox-sensitive cysteine residues of KEAP1, facilitates the dissociation of the KEAP1/CUL3/NRF2 complex, releasing NRF2, which translocates into the nucleus. Once within the nucleus, NRF2 heterodimerically pairs with small Maf transcription factors binding to antioxidant response elements (ARE) contained within the promoter regions of many enzymes, initiating their transcription. (B) ARE-mediated gene products are typically classified as either detoxification or antioxidant enzymes. (Adapted and modified from Dinkova-Kostova and Talalay, 2008).

Figure 3

Summary of interactions and maintenance of vitamins A, C, and E by Sulforaphane-mediated induction of ARE-dependent gene products.