Key Points
-
Members of the cytochrome P450 (CYP) family often catalyse the first step in the detoxification of foreign substances — xenobiotics — that are ingested in our diet, breathed through the air or absorbed through our skin. CYP3A alone is responsible for the metabolism of 50–60% of all prescription drugs.
-
The expression of the genes that code for many of the CYPs that are involved in xenobiotic metabolism can be induced by xenobiotics. Although this represents an adaptive response to protect against chemical exposure, it is also the basis for an important class of drug–drug interactions, as drugs that induce CYP gene expression accelerate the metabolism of many other medications.
-
The pregnane X receptor (PXR) is a ligand-dependent transcription factor that is activated by a wide range of chemicals, including glucocorticoids, antiglucocorticoids, macrocyclic antibiotics, antifungals and herbal extracts, which have no obvious structural features in common. PXR is now widely accepted as the principal transcriptional regulator of CYP3A induction by xenobiotics.
-
The constitutive androstane receptor (CAR) regulates the expression of CYP2B, which has a more minor role in drug metabolism than CYP3A. Data indicate that there is crosstalk between CAR and PXR in the regulation of P450 enzyme expression, although the pharmacological effect of this crosstalk on drug metabolism remains to be determined.
-
The structure of PXR shows several important differences compared with other nuclear receptors, including CAR. In particular, the large, spherical ligand-binding pocket does not require ligands to satisfy a single shape or arrangement of hydrogen-bonding interactions, allowing PXR to recognize a wide range of xenobiotics.
-
Several drug interactions, such as those that involve the psychoactive component of St John's wort, hyperforin, could be attributed to inadvertent activation of PXR. To reduce the possibility of adverse interactions for future drugs, there are several levels at which PXR screening could be used:
-
First, in silico screening — using computational docking of molecules into the PXR crystal structure — could be applied to the design of new combinatorial libraries and to aid in the selection of PXR-transparent building blocks.
-
Second, the development of high-throughput PXR binding assays would allow entire corporate compound collections to be screened. The identification of PXR ligands at this early stage of the drug discovery process will improve the likelihood that the undesired activity can be removed subsequently.
-
Third, PXR cell-based assays can be used during the process of lead optimization to ensure that clinical candidates are unlikely to induce CYP3A in vivo.
-
Last, humanized mice might prove useful in those cases in which the toxicology of PXR activation needs to be documented for risk assessment of human exposure.
Abstract
Mechanisms that protect the body from a diverse array of harmful chemicals are also involved in drug metabolism, and can cause adverse drug–drug interactions. Two closely related orphan nuclear hormone receptors — the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) — have recently emerged as transcriptional regulators of cytochrome P450 expression that couple xenobiotic exposure to oxidative metabolism. In this review, we provide an examination of the roles of PXR and CAR as xenobiotic sensors, and discuss the application of this knowledge to toxicological screening in drug discovery.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Nebert, D. W. & Gonzalez, F. J. P450 genes: structure, evolution, and regulation. Annu. Rev. Biochem. 56, 945–993 (1987).
Nelson, D. R. et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 6, 1–42 (1996).
Denison, M. S. & Whitlock, J. P. Jr. Xenobiotic-inducible transcription of cytochrome P450 genes. J. Biol. Chem. 270, 18175–18178 (1995).
Selye, H. Hormones and resistance. J. Pharm. Sci. 60, 1–28 (1971).
Quattrochi, L. C. & Guzelian, P. S. CYP3A regulation: from pharmacology to nuclear receptors. Drug Metab. Dispos. 29, 615–622 (2001).
Kocarek, T. A., Schuetz, E. G., Strom, S. C., Fisher, R. A. & Guzelian, P. S. Comparative analysis of cytochrome P450 3A induction in primary cultures of rat, rabbit, and human hepatocytes. Drug Metab. Dispos. 23, 415–421 (1995).
Remmer, H. & Merker, H. Drug-induced changes in the liver endoplasmic reticulum — association with drug-metabolizing enzymes. Science 142, 16657–16658 (1963).
Waxman, D. J. & Azaroff, L. Phenobarbital induction of cytochrome P450 gene expression. Biochem. J. 281, 577–592 (1992).
Waxman, D. J. P450 gene induction by structurally diverse xenochemicals: central role of nuclear receptors CAR, PXR, and PPAR. Arch. Biochem. Biophys. 369, 11–23 (1999).
Sueyoshi, T. & Negishi, M. Phenobarbital response elements of cytochrome P450 genes and nuclear receptors. Annu. Rev. Pharmacol. Toxicol. 41, 123–143 (2001).
Okey, A. B. Enzyme induction in the cytochrome P450 system. Pharmacol. Ther. 45, 241–298 (1990).
Michalets, E. L. Update: clinically significant cytochrome P450 drug interactions. Pharmacotherapy 18, 84–112 (1998).
Guengerich, F. P. Cytochrome P450 3A4: regulation and role in drug metabolism. Annu. Rev. Pharmacol. Toxicol. 39, 1–17 (1999).
Li, A. P., Kaminski, D. L. & Rasmussen, A. Substrates of human hepatic cytochrome P450 3A4. Toxicology 104, 1–8 (1995).
Veehof, L. J. G., Stewart, R. E., Meyboom-de Jong, B. & Haaijer-Ruskamp, F. M. Adverse drug reactions and polypharmacy in the elderly in general practice. Eur. J. Clin. Pharmacol. 55, 533–536 (1999).
Kuhlmann, J. & Muck, W. Clinical-pharmacological strategies to assess drug interaction potential during drug development. Drug Saf. 24, 715–725 (2001).
Gronemeyer, H. & Laudet, V. Transcription factors 3: nuclear receptors. Protein Profile 2, 1173–1308 (1995).
Kliewer, S. A., Lehmann, J. M. & Willson, T. M. Orphan nuclear receptors: shifting endocrinology into reverse. Science 284, 757–760 (1999).
Chawla, A., Repa, J. J., Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870 (2001).
Kliewer, S. A. et al. An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92, 73–82 (1998).The first paper to describe the cloning of PXR. The authors showed that PXR is expressed in the liver and intestine, activated by PCN, glucocorticoids and antiglucocorticoids, and binds to a response element that is conserved in CYP3A promoters.
Lehmann, J. M. et al. The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. J. Clin. Invest. 102, 1016–1023 (1998).This paper, together with references 22 and 23 , described the cloning of the human orthologue of PXR, and identified its role in mediating many common drug–drug interactions.
Bertilsson, G. et al. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc. Natl Acad. Sci. USA 95, 12208–12213 (1998).See reference 21.
Blumberg, B. et al. SXR, a novel steroid and xenobiotic-sensing nuclear receptor. Genes Dev. 12, 3195–3205 (1998).See reference 20 . The authors also propose that human PXR functions as a promiscuous xenobiotic receptor.
Zhang, H. et al. Rat pregnane X receptor: molecular cloning, tissue distribution, and xenobiotic regulation. Arch. Biochem. Biophys. 368, 14–22 (1999).
Savas, U., Wester, M. R., Griffin, K. J. & Johnson, E. F. Rabbit pregnane X receptor is activated by rifampicin. Drug Metab. Dispos. 28, 529–537 (2000).
Jones, S. A. et al. The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution. Mol. Endocrinol. 14, 27–39 (2000).
Handschin, C., Podvinec, M. & Meyer, U. A. CXR, a chicken xenobiotic-sensing orphan nuclear receptor, is related to both mammalian pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Proc. Natl Acad. Sci. USA 97, 10769–10774 (in the press).
Moore, L. B. et al. PXR, CAR, and BXR define three pharmacologically distinct classes of nuclear receptors. Mol. Endocrinol. (in the press).
Escriva, H., Delaunay, F. & Laudet, V. Ligand binding and nuclear receptor evolution. Bioessays 22, 717–727 (2000).
Zhang, J. et al. The human pregnane X receptor: genomic structure and identification and functional characterization of natural allelic variants. Pharmacogenetics 11, 555–572 (2001).
Hustert, E. et al. Natural protein variants of pregnane X receptor with altered transactivation activity toward CYP3A4. Drug Metab. Dispos. 29, 1454–1459 (2001).
Baes, M. et al. A new orphan member of the nuclear hormone receptor superfamily that interacts with a subset of retinoic acid response elements. Mol. Cell. Biol. 14, 1544–1552 (1994).
Choi, H.-S. et al. Differential transactivation by two isoforms of the orphan nuclear hormone receptor CAR. J. Biol. Chem. 272, 23565–23571 (1997).
Forman, B. M. et al. Androstane metabolites bind to and deactivate the nuclear receptor CAR-β. Nature 395, 612–615 (1998).This paper proposed that the testosterone metabolite 3α,5α-androstanol is a naturally occurring CAR ligand. The androstane decreased the constitutive activity of mouse CAR.
Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835–839 (1995).
Beato, M., Herrlich, P. & Schuetz, G. Steroid hormone receptors: many actors in search of a plot. Cell 83, 851–857 (1995).
Moore, L. B. et al. St John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc. Natl Acad. Aci. USA 97, 7500–7502 (2000). | PubMed |Hyperforin, a constituent of the herbal remedy St John's wort, was shown to be a potent PXR activator. This study provided a molecular mechanism for the interaction of St John's wort with prescription drugs such as oral contraceptives.
Lu, A. Y., Somogyi, A., West, S., Kuntzman, R. & Conney, A. H. Pregnenolone-16α-carbonitrile: a new type of inducer of drug-metabolizing enzymes. Arch. Biochem. Biophys. 152, 457–462 (1972).
Goodwin, B., Hodgson, E. & Liddle, C. The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Mol. Pharmacol. 56, 1329–1334 (1999).
Staudinger, J. L. et al. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl Acad. Sci. USA 98, 3369–3374 (2001).This paper, together with reference 90 , reported that PXR is activated by toxic bile acids and is involved in the metabolism and removal of these harmful chemicals from the body.
Xie, W. et al. Humanized xenobiotic response in mice expressing nuclear receptor SXR. Nature 406, 435–439 (2000).Targeted disruption of the Pxr gene in mice was shown to abolish induction of Cyp3a11 in response to PCN and dexamethasone. Expression of human PXR in the Pxr−/− mice resulted in induction of Cyp3a11 by the human-specific PXR agonist rifampicin. Mice that expressed a constitutively active form of PXR were resistant to the anaesthetic and paralytic effects of the CYP substrates tribromoethanol and zoxazolamine.
Savas, U., Griffin, K. J. & Johnson, E. F. Molecular mechanisms of cytochrome P450 induction by xenobiotics: an expanded role for nuclear hormone receptors. Mol. Pharmacol. 56, 851–857 (1999).
Schuetz, E. G. Induction of cytochromes P450. Curr. Drug Metab. 2, 139–147 (2001).
Zelko, I. & Negishi, M. Phenobarbital-elicited activation of nuclear receptor CAR in induction of cytochrome P450 genes. Biochem. Biophys. Res. Commun. 277, 1–6 (2000).
Honkakoski, P., Zelko, I., Sueyoshi, T. & Negishi, M. The nuclear orphan receptor CAR–retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol. Cell. Biol. 18, 5652–5658 (1998).CAR was shown to bind as a heterodimer with RXR to a phenobarbital response element that is conserved in CYP2B genes. The concentration of CAR in the nuclei of hepatocytes was shown to increase in response to phenobarbital treatment.
Kawamoto, T. et al. Phenobarbital-responsive nuclear translocation of the receptor CAR in induction of the CYP2B gene. Mol. Cell. Biol. 19, 6318–6322 (1999).
Zelko, I., Sueyoshi, T., Kawamoto, T., Moore, R. & Negishi, M. The peptide near the C terminus regulates receptor CAR nuclear translocation induced by xenochemicals in mouse liver. Mol. Cell. Biol. 21, 2838–2846 (2001).
Sueyoshi, T., Kawamoto, T., Zelko, I., Honkakoski, P. & Negishi, M. The repressed nuclear receptor CAR responds to phenobarbital in activating the human CYP2B6 gene. J. Biol. Chem. 274, 6043–6046 (1999).
Tzameli, I., Pissios, P., Schuetz, E. G. & Moore, D. D. The xenobiotic compound 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene is an agonist ligand for the nuclear receptor CAR. Mol. Cell. Biol. 20, 2951–2958 (2000).
Moore, L. B. et al. Orphan nuclear receptors constitutive androstane receptor and pregnane X receptor share xenobiotic and steroid ligands. J. Biol. Chem. 275, 15122–15127 (2000).
Tzameli, I. & Moore, D. D. Role reversal: new insights from new ligands for the xenobiotic receptor CAR. Trends Endocrinol. Metab. 12, 7–10 (2001).
Wei, P., Zhang, J., Egan-Haffley, M., Liang, S. & Moore, D. D. The nuclear receptor CAR mediates specific xenobiotic induction of drug metabolism. Nature 407, 920–923 (2000).Targeted disruption of the Car gene in mice was shown to abolish phenobarbital- and TCPOBOP-induced hepatomegaly and induction of Cyp2b10 expression. Car−/− mice were hypersensitive to paralysis caused by the CYP substrate zoxazolamine.
Weatherman, R. V., Fletterick, R. J. & Scanlan, T. S. Nuclear-receptor ligands and ligand-binding domains. Annu. Rev. Biochem. 68, 559–581 (1999).
Steinmetz, A. C. U., Renaud, J.-P. & Moras, D. Binding of ligands and activation of transcription by nuclear receptors. Annu. Rev. Biophys. Biomol. Struct. 30, 329–359 (2001).
Watkins, R. E. et al. The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity. Science 292, 2329–2333 (2001).This paper described the three-dimensional structure of the PXR ligand-binding domain. The ligand-binding pocket was shown to be large and spherical in character, enabling it to function as a promiscuous xenobiotic receptor.
Wurtz, J.-M. et al. A canonical structure for the ligand-binding domain of nuclear receptors. Nature Struct. Biol. 3, 87–94 (1996).
Gillam, E. M. The PXR ligand-binding domain: how to be picky and promiscuous at the same time. Trends Pharmacol. Sci. 22, 448 (2001).
Dotzlaw, H., Leygue, E., Watson, P. & Murphy, L. C. The human orphan receptor PXR messenger RNA is expressed in both normal and neoplastic breast tissue. Clin. Cancer Res. 5, 2103–2107 (1999).
Rochel, N., Wurtz, J. M., Mitschler, A., Klaholz, B. & Moras, D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol. Cell 5, 173–179 (2000).
Moore, J. T. & Kliewer, S. A. Use of the nuclear receptor PXR to predict drug interactions. Toxicology 153, 1–10 (2000).
Fuhr, U. Induction of drug metabolizing enzymes: pharmacokinetic and toxicological consequences in humans. Clin. Pharmacokinet. 38, 493–504 (2000).
Watkins, P. B. & Whitcomb, R. W. Hepatic dysfunction associated with troglitazone. N. Engl. J. Med. 338, 916–917 (1998).
Yamazaki, H. et al. Oxidation of troglitazone to a quinone-type metabolite catalysed by cytochrome P450 2C8 and P450 3A4 in human liver microsomes. Drug Metab. Dispos. 27, 1260–1266 (1999).
He, K., Woolf, T. F., Kindt, E. K., Fielder, A. E. & Talaat, R. E. Troglitazone quinone formation catalysed by human and rat CYP3A: an atypical CYP oxidation reaction. Biochem. Pharmacol. 62, 191–198 (2001).
Kostrubsky, V. E. et al. Induction of cytochrome P450 3A by taxol in primary cultures of human hepatocytes. Arch. Biochem. Biophys. 15, 131–136 (1998).
Synold, T. W., Dussault, I. & Forman, B. M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med. 7, 584–590 (2001).
LeCluyse, E. L. Human hepatocyte culture systems for the in vitro evaluation of cytochrome P450 expression and regulation. Eur. J. Pharm. Sci. 13, 343–368 (2001).
LeCluyse, E. L. Pregnane X receptor: molecular basis for species differences in CYP3A induction by xenobiotics. Chem. Biol. Interact. 134, 283–289 (2001).
Wentworth, J. M., Agostini, M., Love, J., Schwabe, J. W. & Chatterjee, V. K. K. St John's wort, a herbal antidepressant, activates the steroid X receptor. J. Endocrinol. 166, R11–R16 (2000).
Dussault, I. et al. Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR. J. Biol. Chem. 276, 33309–33312 (2001).
Xie, W. et al. Reciprocal activation of xenobiotic response genes by nuclear receptors SXR/PXR and CAR. Genes Dev. 14, 3014–3023 (2000).
Goodwin, B., Moore, L. B., Stoltz, C. M., McKee, D. D. & Kliewer, S. A. Regulation of the human CYP2B6 gene by the nuclear pregnane X receptor. Mol. Pharmacol. 60, 427–431 (2001).
Handschin, C., Podvinec, M., Stockli, J., Hoffmann, K. & Meyer, U. A. Conservation of signaling pathways of xenobiotic-sensing orphan nuclear receptors, chicken xenobiotic receptor, constitutive androstane receptor, and pregnane X receptor, from birds to humans. Mol. Endocrinol. 15, 1571–1585 (2001).
Smirlis, D., Muangmoonchai, R., Edwards, M., Phillips, I. R. & Shephard, E. A. Orphan receptor promiscuity in the induction of cytochromes P450 by xenobiotics. J. Biol. Chem. 276, 12822–12826 (2001).
Wei, P., Zhang, J., Dowhan, D. H., Han, Y. & Moore, D. D. Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response. Pharmacogenomics J. (in the press) .
Guengerich, F. P. Pharmacogenomics of cytochrome P450 and other enzymes involved in biotransformation of xenobiotics. Drug Dev. Res. 49, 4–16 (2000).
Meyer, U. A. Pharmacogenetics and adverse drug reactions. Lancet 356, 1667–1671 (2000).
Evans, W. E. & Johnson, J. A. Pharmacogenomics: the inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet. 2, 9–39 (2001).
Ekins, S. & Erickson, J. A. A pharmacophore for human pregnane X receptor ligands. Drug Metab. Dispos. 30, 96–99 (2002).
Bohm, H.-J. & Stahl, M. Structure-based library design: molecular modeling merges with combinatorial chemistry. Curr. Opin. Chem. Biol. 4, 283–286 (2000).
Leach, A. R. & Hann, M. M. The in silico world of virtual libraries. Drug Discov Today 5, 326–336 (2000).
Fox, S., Wang, H., Sopchak, L. & Khoury, R. High throughput screening: early successes indicate a promising future. J. Biomol. Screening 6, 137–140 (2001).
Lazar, M. A. Gene regulation: one man's food. Nature 407, 852–853 (2000).
Gillam, E. Transgenic xenosensors: humanizing mice. Trends Pharmacol. Sci. 21, 330–331 (2000).
Maglich, J. M. et al. Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drospohila genomes. Genome Biol. [online] (cited 12 Feb 2002) 〈http://genomebiology.com/2001/2/8/research/0029/〉 (2001).
Muerhoff, A. S., Griffin, K. J. & Johnson, E. F. The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid ω-hydroxylase, by clofibric acid. J. Biol. Chem. 267, 19051–19053 (1992).
Kroetz, D. L., Yook, P., Costet, P., Bianchi, P. & Pineau, T. Peroxisome proliferator-activated receptor α controls the hepatic CYP4A induction adaptive response to starvation and diabetes. J. Biol. Chem. 273, 31581–31589 (1998).
Takeyama, K. et al. 25-Hydroxyvitamin D3 1α-hydroxylase and vitamin D synthesis. Science 277, 1827–1830 (1997).
Murayama, A. et al. The promoter of the human 25-hydroxyvitamin D3 1α-hydroxylase gene confers positive and negative responsiveness to PTH, calcitonin, and 1α,25(OH)2D3 . Biochem. Biophys. Res. Commun. 249, 11–16 (1998).
Xie, W. et al. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc. Natl Acad. Sci. USA 98, 3375–3380 (2001).See reference 40.
Ueda, A. et al. Diverse roles of the nuclear orphan receptor CAR in regulating hepatic genes in response to phenobarbital. Mol. Pharmacol. 61, 1–6 (2002).
Willson, T. M., Jones, S. A., Moore, J. T. & Kliewer, S. A. Chemical genomics: functional analysis of orphan nuclear receptors in the regulation of bile acid metabolism. Med. Res. Rev. 21, 513–522 (2001).
Geick, A., Eichelbaum, M. & Burk, O. Nuclear receptor response elements mediate induction of intestinal MDR1 by rifampin. J. Biol. Chem. 276, 14581–14587 (2001).
Guo, G. L., Choudhuri, S. & Klaassen, C. D. Induction profile of rat organic anion transporting polypeptide 2 (Oatp2) by prototypical drug-metabolizing enzyme inducers that activate gene expression through ligand-activated transcription factor pathways. J. Pharmacol. Exp. Ther. 300, 206–212 (2002).
Kast, H. R. et al. Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X receptor, and constitutive androstane receptor. J. Biol. Chem. 277, 2908–2915 (2002).
Borst, P., Evers, R., Kool, M. & Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl Cancer Inst. 92, 1295–1302 (2000).
Gao, B. & Meier, P. J. Organic anion transport across the choroid plexus. Microsc. Res. Tech. 52, 60–64 (2001).
Kerb, R., Hoffmeyer, S. & Brinkmann, U. ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2. Pharmacogenomics 2, 51–64 (2001).
Suzuki, H. & Sugiyama, Y. Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur. J. Pharm. Sci. 12, 3–12 (2000).
Hofmann, A. F. The continuing importance of bile acids in liver and intestinal disease. Arch. Intern. Med. 159, 2647–2658 (1999).
Staudinger, J., Liu, Y., Madan, A., Habeebu, S. & Klaassen, C. D. Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab. Dispos. 29, 1467–1472 (2001).
Chevallier, A. The Encyclopedia of Medicinal Plants (Dorling Kindersley, New York, 1996).
Nuclear Receptors Committee. A unified nomenclature system for the nuclear receptor superfamily. Cell 97, 161–163 (1999).
Author information
Authors and Affiliations
Corresponding author
Related links
Related links
DATABASES
LocusLink
Medscape DrugInfo
<I>Saccharomyces</I> Genome Database
FURTHER INFORMATION
Encyclopedia of Life Sciences
Glossary
- XENOBIOTICS
-
Molecules ingested in food, water or air, which include environmental toxins and synthetic drug molecules. Organisms have evolved a series of defence mechanisms to protect them from the harmful effects of xenobiotics. One of the primary mechanisms is oxidative metabolism, which occurs in the liver and intestine.
- LIPOPHILIC
-
Literally, 'fat loving'. Applied to compounds (or parts of compounds) that have a tendency to dissolve in fat-like (for example, hydrocarbon) solvents. Lipophilic compounds will therefore accumulate in the lipid membrane of cells.
- MONOOXYGENASE
-
An oxidoreductase enzyme that brings about the incorporation of one atom of oxygen (for example, as a part of a hydroxyl group) from O2 into a compound.
- HEPATOMEGALY
-
Inflammation of the liver.
- VAN DER WAALS INTERACTION
-
A van der Waals interaction is a weak attractive force that acts between non-bonded atoms or molecules. It accounts for the attraction of hydrophobic molecules to each other.
- SCINTILLATION PROXIMITY ASSAY
-
Uses microscopic beads that contain a scintillant that can be stimulated to emit light. This stimulation event occurs only when radiolabelled molecules of interest are bound to the surface of the bead. A range of bead coatings allows bead types to be manufactured for specific applications, including screening for receptor–ligand binding, protein–protein interactions and protein–DNA interactions.
- ANTIMYCOTIC
-
A substance that is used to kill a fungus or to inhibit its growth.
Rights and permissions
About this article
Cite this article
Willson, T., Kliewer, S. Pxr, car and drug metabolism. Nat Rev Drug Discov 1, 259–266 (2002). https://doi.org/10.1038/nrd753
Issue Date:
DOI: https://doi.org/10.1038/nrd753
This article is cited by
-
Cocaine regulates antiretroviral therapy CNS access through pregnane-x receptor-mediated drug transporter and metabolizing enzyme modulation at the blood brain barrier
Fluids and Barriers of the CNS (2024)
-
Evaluation of the Effect of Lorlatinib on CYP2B6, CYP2C9, UGT, and P-Glycoprotein Substrates in Patients with Advanced Non-Small Cell Lung Cancer
Clinical Pharmacokinetics (2024)
-
2′,3′,4′-Trihydroxychalcone changes estrogen receptor α regulation of genes and breast cancer cell proliferation by a reprogramming mechanism
Molecular Medicine (2022)
-
Label-free chemical imaging of cytochrome P450 activity by Raman microscopy
Communications Biology (2022)
-
An approach for mixture testing and prioritization based on common kinetic groups
Archives of Toxicology (2022)