Phytochemical Regulation of UDP-Glucuronosyltransferases: Implications for Cancer Prevention

Abstract

Uridine 5′-diphospho-glucuronosyltransferases (UGTs) are Phase II biotransformation enzymes that metabolize endogenous and exogenous compounds, some of which have been associated with cancer risk. Many phytochemicals have been shown to induce UGTs in humans, rodents, and cell culture systems. Because UGTs maintain hormone balance and facilitate excretion of potentially carcinogenic compounds, regulation of their expression and activity may affect cancer risk. Phytochemicals regulate transcription factors such as the nuclear factor-erythroid 2-related factor 2 (Nrf2), aryl hydrocarbon, and pregnane X receptors as well as proteins in several signal transduction cascades that converge on Nrf2 to stimulate UGT expression. This induction can be modified by several factors, including phytochemical dose and bioavailability and interindividual variation in enzyme expression. In this review, we summarize the knowledge of dietary modulation of UGTs, particularly by phytochemicals, and discuss the potential mechanisms by which phytochemicals regulate UGT transcription.

Acknowledgments and Notes

Grant support is from the National Cancer Institute training Grant R25 CA94880. We thank Clayton Hibbert for his help designing the figure for this article and Lewis Chang and Yu Chen at the Fred Hutchinson Cancer Research Center for their helpful comments and feedback.

Notes

^a : Abbreviations are as follows: UGTs, Uridine 5′-diphospho-glucuronosyltransferases; AP, 2-aminophenol; BITC, benzylisothiocyanate; CA, cholorogenic acid; CHLOR, chloramphenicol; d, day; DADS, diallyl disulfide; DAS, diallyl sulfide; DPDS, dipropyl disulfide; DPS, dipropyl sulfide; EA, ellagic acid; FA, ferulic acid; IQ, 2-amino-3-methylimidazo-[4,5-f]-quinoline; ITC, isothiocyanate; I3C, indole-3-carbinol; Misc, miscellaneous; mo, month; MPA, mycophenolic acid; 4-MUB, 4-methylumbelliferone; PCA, protocatechuic acid; PEITC, phenylethyl isothiocyanate; PHBP, 4-hydroxybiphenyl; PhIP, 2-amino-1-methyl-6-phenyl-imidazo-[4,5-b]pyridine; PNP, P-nitrophenol; RA, retinoic acid; SFN, sulforaphane; T3, thyroxine; T4, triiodo-L-thyronine; wk, week; Nrf2, nuclear factor-erythroid 2-related factor 2; RT-PCR, reverse transcriptase polymerase chain reaction;.

^b : Given in diet unless otherwise indicated.

^a : Abbreviations are as follows: UGTs, Uridine 5′-diphospho-glucuronosyltransferases; BTP, black tea polyphenols; E3, estradiol-3; E17, estradiol-17; EE, ethinyl-estradiol; EGCG, epigallocatechin gallate; GTP, green tea polyphenols; 3-HBP, 3-hydroxy-benzo[a]pyrene; ITC, isothiocyanate; MPA, mycophenolic acid; 4-MUB, 4-methylumbelliferone; NDGA, nordihydroguaiaretic acid; N-2-amino-1-methyl-6-phenyl-imidazo-[4,5-b]pyridine (PhIP), N-hydroxy-PhIP; PNP, p-nitrophenol; RA, retinoic acid; RT-PCR, reverse transcriptase polymerase chain reaction; SFN, sulforaphane.

b: Real-time RT-PCR.