Genes and Glutathione

Genetic influences

Once absorbed, glucosinolate-derived isothiocyanates (like sulforaphane) are promptly conjugated to glutathione by a class of phase II detoxification enzymes known as glutathione S-transferases (GSTs) (Figure 3). This mechanism is meant to increase the solubility of isothiocyanates, thereby promoting a rapid excretion in the urine. Isothiocyanates are thought to play a prominent role in the potential anticancer and cardiovascular benefits associated with cruciferous vegetable consumption (12, 13). Genetic variations in the sequence of genes coding for GSTs may affect the activity of these enzymes. Such variations have been identified in humans. Specifically, null variants of the GSTM1 and GSTT1 alleles contain large deletions, and individuals who inherit two copies of the GSTM1-null or GSTT1-null alleles cannot produce the corresponding GST enzymes (14). It has been proposed that a reduced GST activity in these individuals would slow the rate of excretion of isothiocyanates, thereby increasing tissue exposure to isothiocyanates after cruciferous vegetable consumption (15). However, human interventional studies with watercress report there is no difference in the isothiocyanate excretion rate between positive (+/+) and null (-/-) genotypes (16). Similar studies with broccoli have shown that GSTM1-/- individuals excreted a greater proportion of ingested sulforaphane via mercapturic acid metabolism than GSTM1+/+ individuals (17, 18). In addition, GSTs are involved in “detoxifying” potentially harmful substances like carcinogens, suggesting that individuals with reduced GST activity might also be more susceptible to cancer (19-21). Finally, induction of the expression and activity of GSTs and other phase II detoxification/antioxidant enzymes by isothiocyanates is an important defense mechanism against oxidative stress and damage associated with the development of diseases like cancer and cardiovascular disease (22). The ability of sulforaphane (glucoraphanin-derived isothiocyanate) to reduce oxidative stress in different settings is linked to activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway. Yet, whether potential protection conferred by isothiocyanates via the Nrf2-dependent pathway is diminished in individuals carrying GST-/- variants is currently unknown.

Some, but not all, observational studies have found that GST genotypes could influence the associations between isothiocyanate intake from cruciferous vegetables and risk of disease (23).

12.  Bai Y, Wang X, Zhao S, Ma C, Cui J, Zheng Y. Sulforaphane protects against cardiovascular disease via Nrf2 activation. Oxid Med Cell Longev. 2015;2015:407580.  (PubMed)

13.  Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007;55(3):224-236.  (PubMed)

14.  Coles BF, Kadlubar FF. Detoxification of electrophilic compounds by glutathione S-transferase catalysis: determinants of individual response to chemical carcinogens and chemotherapeutic drugs? Biofactors. 2003;17(1-4):115-130.  (PubMed)

15.  Seow A, Shi CY, Chung FL, et al. Urinary total isothiocyanate (ITC) in a population-based sample of middle-aged and older Chinese in Singapore: relationship with dietary total ITC and glutathione S-transferase M1/T1/P1 genotypes. Cancer Epidemiol Biomarkers Prev. 1998;7(9):775-781.  (PubMed)

16.  Dyba M, Wang A, Noone AM, et al. Metabolism of isothiocyanates in individuals with positive and null GSTT1 and M1 genotypes after drinking watercress juice. Clin Nutr. 2010;29(6):813-818.  (PubMed)

17.  Gasper AV, Al-Janobi A, Smith JA, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr. 2005;82(6):1283-1291.  (PubMed)

18.  Steck SE, Gammon MD, Hebert JR, Wall DE, Zeisel SH. GSTM1, GSTT1, GSTP1, and GSTA1 polymorphisms and urinary isothiocyanate metabolites following broccoli consumption in humans. J Nutr. 2007;137(4):904-909.  (PubMed)

19.  Economopoulos KP, Sergentanis TN. GSTM1, GSTT1, GSTP1, GSTA1 and colorectal cancer risk: a comprehensive meta-analysis. Eur J Cancer. 2010;46(9):1617-1631.  (PubMed)

20.  Egner PA, Chen JG, Zarth AT, et al. Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prev Res (Phila). 2014;7(8):813-823.  (PubMed)

21.  Sergentanis TN, Economopoulos KP. GSTT1 and GSTP1 polymorphisms and breast cancer risk: a meta-analysis. Breast Cancer Res Treat. 2010;121(1):195-202.  (PubMed)

22.  Bryan HK, Olayanju A, Goldring CE, Park BK. The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation. Biochem Pharmacol. 2013;85(6):705-717.  (PubMed)

23.  Traka MH. Chapter nine – Health benefits of glucosinolates. Advances in Botanical Research. 2016;80:247-279.

24.  Nothlings U, Schulze MB, Weikert C

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