Abstract
Hops extracts are used to alleviate menopausal symptoms and as an alternative to hormone replacement therapy, but they can produce potentially harmful drug-drug interactions. The nuclear xenobiotic receptor pregnane X receptor (PXR) is promiscuously activated by a range of structurally distinct chemicals. It has a key role in the transcriptional regulation of genes that encode xenobiotic metabolism enzymes. In this study, hops extracts are shown to induce the expression of numerous drug metabolism and excretion proteins. The beta-bitter acid colupulone is demonstrated to be a bioactive component and direct activator of human PXR. The 2.8-A resolution crystal structure of the ligand binding domain of human PXR in complex with colupulone was elucidated, and colupulone was observed to bind in a single orientation stabilized by both van der Waals and hydrogen bonding contacts. The crystal structure also indicates that related alpha- and beta-bitter acids have the capacity to serve as PXR agonists as well. Taken together, these results reveal the structural basis for drug-drug interactions mediated by colupulone and related constituents of hops extracts.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
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Aryl Hydrocarbon Hydroxylases / biosynthesis
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Binding Sites
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Crystallography, X-Ray
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Cyclohexanones / chemistry
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Cyclohexanones / pharmacology*
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 CYP3A / biosynthesis
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Humans
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Humulus*
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In Vitro Techniques
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Oxidoreductases, N-Demethylating / biosynthesis
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Plant Extracts / chemistry
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Plant Extracts / pharmacology
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Pregnane X Receptor
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RNA, Messenger / biosynthesis
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Receptors, Steroid / agonists*
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Receptors, Steroid / chemistry
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Up-Regulation
Substances
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ABCB1 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Cyclohexanones
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Plant Extracts
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Pregnane X Receptor
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RNA, Messenger
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Receptors, Steroid
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colupulone
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Aryl Hydrocarbon Hydroxylases
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CYP2B6 protein, human
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Cytochrome P-450 CYP2B6
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Oxidoreductases, N-Demethylating