AbstractUDP-glucuronosyltransferases (UGTs) are important detoxification and drug-metabolizing enzymes, which catalyse the glucuronidation of exogenous and endogenous chemicals. The anti-carcinogenic activity of dietary phytochemicals is partly attributed to the induction of phase II enzymes, including UGT1A. Our earlier study showed that protocatechuic acid increased UGT activity in rat liver. A similar effect was observed for indole-3-carbinol and phenethyl isothiocyanate in rat liver. In this study we assessed the effect of protocatechuic acid, tannic acid, indole-3-carbinol and phenethyl isothiocyanate on the expression and protein level of UGT1A in hepatocellular carcinoma HepG2 cells. Cells were incubated with 2µM and 10µM of protocatechuic acid, tannic acid, or indole-3-carbinol and 1µM and 5µM of phenethyl isothiocyanate for 72 hours. Transcript level was measured by RT-PCR and protein level by the immunoblot assay. Treatment with protocatechuic acid, tannic acid, indole-3-carbinol and phenethyl isothiocyanate induced the expression and protein level of UGT1A. Phenethyl isothiocyanate increased the mRNA of UGT1A to the most extent (0.28–5.7 fold change, p < 0.05). Increased expression of UGT1A was accompanied by the enhancement of its protein level, with the exception of protocatechuic acid at the dose of 2µM. Overall, isothiocyanates and indoles were more potent as UGT inducers than phenolic acids. Collectively, the results suggest that the induction of UGT1A could contribute to the hepatoprotective and chemopreventive properties of these phytochemicals.
Download data is not yet available.
- Saracino MR, Lampe JW. Phytochemical regulation of UP-glucuronosyltransferase: implications for cancer prevention. Nutr. Cancer. 2007 Dec;59(2):121–41.
- Owens IS, Basu NK, Banerjee R. UP-glucuronosyltransferases: gene structures of UT1 and UT2 families. Methods Enzymol. 2005 Dec;400(2):1–22.
- Tukey RH, Strassburg CP. Human UP-glucuronosyltransferases: metabolism, expression and disease. Ann Rev Pharmacol Toxicol. 2000 Apr;40:581–616.
- Pantuck EJ, Hsiao KC, Loub WD, Wattenberg LW, Kuntzman R. Stimulatory effect of vegetables on intestinal drug metabolism in the rat. JPharmacol Exp Ther. 1976 Aug;198(2): 278–83.
- Navarro SL, Peterson S, Chen C, Makar KW, Schwarz Y, King IB et al. Cruciferous vegetable feeding alters UT1A1 activity: diet- and genotype-dependent changes in serum bilirubin in a controlled feeding trial. Cancer Prev Res (Phila). 2009 Apr;2(4):345–52.
- Higdon JV, Delage B, Williams DE, Dashwodd RH. Cruciferous vegetables and human cancer risk: epidemiologic evidence and mechanistic basis. Pharmacol Res. 2007 Mar;55(3):224–36.
- Robbins MG, Hauder J, Somoza V, Eshelman BD, Barnes DM, Hanlon PR. Induction of detoxification enzymes by feeding unblanched Brussels sprouts containing active myrosinase to mice for 2 wk. JFood Sci. 2010 Aug 1;75(6):H190–9.
- Taioli E, Garbers S, Bradlow HL, Carmella SG, Akerkar S, Hecht SS. Effects of indole-3-carbinol on the metabolism of 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone in smokers. Cancer Epidemiol Biomarkers Prev. 1997 Jul;6(7):517–22.
- Shertzer HG, Sainsbury M. Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats. Food Chem Toxicol. 1991 Jun;29(6):391–400.
- Dingley KH, Ubick EA, Chiarappa-Zucca ML, Nowell S, Abel S, Ebeler SE, et.al. Effect of dietary constituents with chemopreventive potential on adduct formation of low dose of the heterocyclic amines PIP and IQ and phase II hepatic enzymes. Nutr Cancer. 2003;46(2):212–21.
- Szaefer H, Cichocki M, Brauze D, Baer-Dubowska W. Alteration in phase I and II enzyme activities and polycyclic aromatic hydrocarbons-DA adduct formation by plant phenolics in mouse epidermis. Nutr Cancer. 2004;48(1):70–7.
- der Loght EJ, Roelofs HJ, Nanengast FM, Peters WM. Induction of rat hepatic and intestinal UP-glucuronosyltransferases by naturally occurring dietary anticarcinogens. Carcinogenesis. 2003 Oct;24(10):1651–6.
- Telang U, Morris ME. Effect of orally administered phenethyl isothiocyanate on hepatic gene expression in rats. Mol Nutr Food Res. 2010 Dec;54(12):1802–6.
- Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. JBiol Chem. 1951 Nov;193(1):265–75.
- Terry P, Terry JB, Wolk A. Fruit and vegetable consumption in the prevention of cancer: an update. JIntern Med. 2001 Oct;250(4):280–90.
- Fattahi S, Zabihi E, Abedian Z, Pourbagher R, Motevalizadeh Ardekani A et al. Total Phenolic and Flavonoid Contents of Aqueous Extract of Stinging Nettle and In Vitro Antiproliferative Effect on Hela and BT-474 Cell Lines. Int JMol Cell Med. 2014 Spring;3(2):102–7.
- Koushik A, Hunter DJ, Spiegelman D, Beeson WL, van den Brandt PA, Buring JE et al. Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies. JNatl Cancer Inst. 2007 Oct 3;99(19):1471–83.
- Lam TK, Gallicchio L, Lindsley K, Shields M, Hammond E, Tao XG et al. Cruciferous vegetable consumption and lung cancer risk: a systematic review. Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):184–95.
- Lasker J, Rickert DE. Absorption and glucuronylation of diethylstilbestrol by the rat small intestine. Xenobiotica. 1978 Nov;8(11):665–72.
- Peters WM, Nagengast FM, van Tongeren JM. Glutathione S-transferase, cytochrome P450 and uridine 5'-diphosphateglucuronosyltransferase in human small intestine and liver. Gastroenterology. 1989 Mar;96(3):783–9.
- Steinmetz KA, Potter JD. Vegetables, fruit and cancer. II. Mechanisms. Cancer Causes Control. 1991 Nov;2(6):427–42.
- Hu Z, Wells PG. Modulation of benzo[a]pyrene bioactivation by glucuronidation in lymphocytes and hepatic microsomes from rats with a hereditary deficiency in bilirubin UP-glucuronosyltransferase. Toxicol Appl Pharmacol. 1994 Aug;127(2):306–13.
- Hu Z, Wells PG. In vitro and in vivo biotransformation and covalent binding of benzo(a)pyrene in Gunn and RA rats with a genetic deficiency in bilirubin uridine diphosphate-glucuronosyltransferase. JPharmacol Exp Ther 1992 Oct;263(1):334–42.
- Berges R, Siess MH, Arnault I, Auger J, Kahane R, Pinnert MF et al. Comparison of the chemopreventive efficacies of garlic powders with different alliin contents against aflatoxin B1 carcinogenicity in rats. Carcinogenesis. 2004 Oct;25(10):1953–9.
- Bu-Abbas A, Clifford MN, Ioannides C, Walker R. Stimulation of rat hepatic UP-glucuronosyltransferase activity following treatment with green tea. Food Chem Toxicol. 1995 Jan;33(1):27–30.
- Bu-Abbas A, Clifford MN, Walker R, Ioannides C. Contribution of caffeine and flavanols in the induction of hepatic phase II activities by green tea. Food Chem Toxicol. 1998 Aug;36(8):617–21.
- Bianchini F, Vainio H. Isothiocyanates in cancer prevention. Drug Metab Rev. 2004 Oct;36(3–4):655–67.
- Conaway CC, Yang YM, Chung FL. Isothiocyanates as cancer chemopreventive agents: their biological activities and metabolism in rodents and humans. Curr Drug Metab. 2002 Jun;3(3):233–55.
- Xu M, Bailey AC, Hernaez JF, Taoka CR, Schut HA, Dashwood RH. Protection by green tea, black tea, and indole-3-carbinol against 2-amino-3-methylimidazo[4,5-f]quinoline-induced DA adducts and colonic aberrant crypts in the F344 rat. Carcinogenesis. 1996 Jul;17(7):1429–34.
- Krajka-Kuźniak V, Szaefer H, Baer-Dubowska W. Modulation of cytochrome P450 and phase II enzymes by protocatechuic acid in mouse liver and kidney. Toxicology. 2005 Dec;216(1):24–31.
- Talalay P. Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 2000 Jan;12(1–4):5–11.
- Krajka-Kuźniak V, Szaefer H, Bartoszek A, Baer-Dubowska W. Modulation of rat hepatic and kidney phase II enzymes by cabbage juices: comparison with the effects of indole-3-carbinol and phenethyl isothiocyanate. Br JNutr. 2011 Mar;105(6):816–26.