Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation

Brandon T Gufford; Gang Chen; Philip Lazarus; Tyler N Graf; Nicholas H Oberlies; Mary F Paine

doi:10.1124/dmd.114.059451

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Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation

Journal article

Open access

Peer reviewed

Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation

Brandon T Gufford, Gang Chen, Philip Lazarus, Tyler N Graf, Nicholas H Oberlies and Mary F Paine

Drug metabolism and disposition, Vol.42(10), pp.1675-1683

10/2014

DOI: https://doi.org/10.1124/dmd.114.059451

Handle:

https://hdl.handle.net/2376/106329

PMCID: PMC4164973

PMID: 25008344

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https://doi.org/10.1124/dmd.114.059451View

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Abstract

Beverages - adverse effects

Intestines - drug effects

Cell Line

Microsomes - metabolism

Citrus paradisi - adverse effects

Diet - adverse effects

Humans

Enzyme Inhibitors - pharmacology

Intestines - metabolism

Xenobiotics - pharmacology

Drug Interactions

Glucuronosyltransferase - antagonists & inhibitors

Hymecromone - pharmacokinetics

Inhibitory Concentration 50

Silymarin - pharmacology

Drug-metabolizing enzymes within enterocytes constitute a key barrier to xenobiotic entry into the systemic circulation. Furanocoumarins in grapefruit juice are cornerstone examples of diet-derived xenobiotics that perpetrate interactions with drugs via mechanism-based inhibition of intestinal CYP3A4. Relative to intestinal CYP3A4-mediated inhibition, alternate mechanisms underlying dietary substance-drug interactions remain understudied. A working systematic framework was applied to a panel of structurally diverse diet-derived constituents/extracts (n = 15) as inhibitors of intestinal UDP-glucuronosyl transferases (UGTs) to identify and characterize additional perpetrators of dietary substance-drug interactions. Using a screening assay involving the nonspecific UGT probe substrate 4-methylumbelliferone, human intestinal microsomes, and human embryonic kidney cell lysates overexpressing gut-relevant UGT1A isoforms, 14 diet-derived constituents/extracts inhibited UGT activity by >50% in at least one enzyme source, prompting IC(50) determination. The IC(50) values of 13 constituents/extracts (≤10 μM with at least one enzyme source) were well below intestinal tissue concentrations or concentrations in relevant juices, suggesting that these diet-derived substances can inhibit intestinal UGTs at clinically achievable concentrations. Evaluation of the effect of inhibitor depletion on IC(50) determination demonstrated substantial impact (up to 2.8-fold shift) using silybin A and silybin B, two key flavonolignans from milk thistle (Silybum marianum) as exemplar inhibitors, highlighting an important consideration for interpretation of UGT inhibition in vitro. Results from this work will help refine a working systematic framework to identify dietary substance-drug interactions that warrant advanced modeling and simulation to inform clinical assessment.

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Title: Identification of diet-derived constituents as potent inhibitors of intestinal glucuronidation
Creators: Brandon T Gufford - Section of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
Gang Chen - Section of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
Philip Lazarus - Section of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
Tyler N Graf - Section of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
Nicholas H Oberlies - Section of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.)
Mary F Paine - Section of Experimental and Systems Pharmacology (B.T.G., M.F.P.) and Department of Pharmaceutical Sciences (G.C., P.L.), Washington State University College of Pharmacy, Spokane, Washington; and Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina (T.N.G., N.H.O.) mary.paine@wsu.edu
Publication Details: Drug metabolism and disposition, Vol.42(10), pp.1675-1683
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01-GM077482-S1 / NIGMS NIH HHS R01 GM077482 / NIGMS NIH HHS
Identifiers: 99900546928501842
Language: English
Resource Type: Journal article