Optical Isomers of Atorvastatin, Rosuvastatin and Fluvastatin Enantiospecifically Activate Pregnane X Receptor PXR and Induce CYP2A6, CYP2B6 and CYP3A4 in Human Hepatocytes
Jazyk angličtina Země Spojené státy americké Médium electronic-ecollection
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
26366873
PubMed Central
PMC4569258
DOI
10.1371/journal.pone.0137720
PII: PONE-D-15-33169
Knihovny.cz E-zdroje
- MeSH
- atorvastatin farmakologie MeSH
- cytochrom P-450 CYP3A biosyntéza MeSH
- cytochrom P450 CYP2A6 biosyntéza MeSH
- cytochrom P450 CYP2B6 biosyntéza MeSH
- dospělí MeSH
- enzymová indukce účinky léků MeSH
- fluvastatin MeSH
- hepatocyty cytologie enzymologie MeSH
- indoly farmakologie MeSH
- induktory cytochromu P450 CYP2B6 farmakologie MeSH
- induktory cytochromu P450 CYP3A farmakologie MeSH
- kyseliny mastné mononenasycené farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- pregnanový X receptor MeSH
- rosuvastatin kalcium farmakologie MeSH
- senioři MeSH
- stereoizomerie MeSH
- steroidní receptory biosyntéza MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- atorvastatin MeSH
- CYP2A6 protein, human MeSH Prohlížeč
- CYP2B6 protein, human MeSH Prohlížeč
- CYP3A4 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP3A MeSH
- cytochrom P450 CYP2A6 MeSH
- cytochrom P450 CYP2B6 MeSH
- fluvastatin MeSH
- indoly MeSH
- induktory cytochromu P450 CYP2B6 MeSH
- induktory cytochromu P450 CYP3A MeSH
- kyseliny mastné mononenasycené MeSH
- pregnanový X receptor MeSH
- rosuvastatin kalcium MeSH
- steroidní receptory MeSH
Atorvastatin, fluvastatin and rosuvastatin are drugs used for treatment of hypercholesterolemia. They cause numerous drug-drug interactions by inhibiting and inducing drug-metabolizing cytochromes P450. These three statins exist in four optical forms, but they are currently used as enantiopure drugs, i.e., only one single enantiomer. There are numerous evidences that efficacy, adverse effects and toxicity of drugs may be enantiospecific. Therefore, we investigated the effects of optical isomers of atorvastatin, fluvastatin and rosuvastatin on the expression of drug-metabolizing P450s in primary human hepatocytes, using western blots and RT-PCR for measurement of proteins and mRNAs, respectively. The activity of P450 transcriptional regulators, including pregnane X receptor (PXR), aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR), was assessed by gene reporter assays and EMSA. Transcriptional activity of AhR was not influenced by any statin tested. Basal transcriptional activity of GR was not affected by tested statins, but dexamethasone-inducible activity of GR was dose-dependently and enantioselectively inhibited by fluvastatin. Basal and ligand-inducible transcriptional activity of PXR was dose-dependently influenced by all tested statins, and the potency and efficacy between individual optical isomers varied depending on statin and optical isomer. The expression of CYP1A1 and CYP1A2 in human hepatocytes was not influenced by tested statins. All statins induced CYP2A6, CYP2B6 and CYP3A4, and the effects on CYP2C9 were rather modulatory. The effects varied between statins and enantiomers and induction potency decreased in order: atorvastatin (RR>RS = SR>SS) > fluvastatin (SR>RS = SS>RR) >> rosuvastatin (only RS active). The data presented here might be of toxicological and clinical importance.
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Smith SW (2009) Chiral Toxicology: It's the Same Thing … Only Different. Toxicological Sciences 110: 4–30. 10.1093/toxsci/kfp097 PubMed DOI
Bellosta S, Corsini A (2012) Statin drug interactions and related adverse reactions. Expert Opinion on Drug Safety 11: 933–946. 10.1517/14740338.2012.712959 PubMed DOI
Neuvonen PJ, Niemi M, Backman JT (2006) Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80: 565–581. PubMed
Hsyu PH, Schultz-Smith MD, Lillibridge JH, Lewis RH, Kerr BM (2001) Pharmacokinetic interactions between nelfinavir and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors atorvastatin and simvastatin. Antimicrobial Agents and Chemotherapy 45: 3445–3450. PubMed PMC
Prueksaritanont T, Ma B, Tang CY, Meng Y, Assang C, Lu P, et al. (1999) Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations. British Journal of Clinical Pharmacology 47: 291–298. PubMed PMC
Scripture CD, Pieper JA (2001) Clinical pharmacokinetics of fluvastatin. Clinical Pharmacokinetics 40: 263–281. PubMed
Olsson AG, McTaggart F, Raza A (2002) Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev 20: 303–328. PubMed
Cooper KJ, Martin PD, Dane AL, Warwick MJ, Schneck DW, Cantarini MV (2003) Effect of itraconazole on the pharmacokinetics of rosuvastatin. Clinical Pharmacology & Therapeutics 73: 322–329. PubMed
Cooper KJ, Martin PD, Dane AL, Warwick MJ, Raza A, Schneck DW (2003) Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects. British Journal of Clinical Pharmacology 55: 94–99. PubMed PMC
Yamasaki D, Nakamura T, Okamura N, Kokudai M, Inui N, Takeuchi K, et al. (2009) Effects of acid and lactone forms of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on the induction of MDR1 expression and function in LS180 cells. European Journal of Pharmaceutical Sciences 37: 126–132. 10.1016/j.ejps.2009.01.009 PubMed DOI
Howe K, Sanat F, Thumser AE, Coleman T, Plant N (2011) The statin class of HMG-CoA reductase inhibitors demonstrate differential activation of the nuclear receptors PXR, CAR and FXR, as well as their downstream target genes. Xenobiotica 41: 519–529. 10.3109/00498254.2011.569773 PubMed DOI
Hoffart E, Ghebreghiorghis L, Nussler AK, Thasler WE, Weiss TS, Schwab M, et al. (2012) Effects of atorvastatin metabolites on induction of drug-metabolizing enzymes and membrane transporters through human pregnane X receptor. British Journal of Pharmacology 165: 1595–1608. 10.1111/j.1476-5381.2011.01665.x PubMed DOI PMC
Plee-Gautier E, Antoun J, Goulitquer S, Le Jossic-Corcos C, Simon B, Amet Y, et al. (2012) Statins increase cytochrome P450 4F3-mediated eicosanoids production in human liver cells: A PXR dependent mechanism. Biochemical Pharmacology 84: 571–579. 10.1016/j.bcp.2012.05.012 PubMed DOI
Kocarek TA, Dahn MS, Cai HB, Strom SC, Mercer-Haines NA (2002) Regulation of CYP2B6 and CYP3A expression by hydroxymethylglutaryl coenzyme a inhibitors in primary cultured human hepatocytes. Drug Metabolism and Disposition 30: 1400–1405. PubMed
Novotna A, Korhonova M, Bartonkova I, Soshilov AA, Denison MS, Bogdanova K, et al. (2014) Enantiospecific Effects of Ketoconazole on Aryl Hydrocarbon Receptor. Plos One 9. PubMed PMC
Novotna A, Krasulova K, Bartonkova I, Korhonova M, Bachleda P, Anzenbacher P, et al. (2014) Dual Effects of Ketoconazole cis-Enantiomers on CYP3A4 in Human Hepatocytes and HepG2 Cells. Plos One 9. PubMed PMC
Rulcova A, Prokopova I, Krausova L, Bitman M, Vrzal R, Dvorak Z, et al. (2010) Stereoselective interactions of warfarin enantiomers with the pregnane X nuclear receptor in gene regulation of major drug-metabolizing cytochrome P450 enzymes. J Thromb Haemost 8: 2708–2717. 10.1111/j.1538-7836.2010.04036.x PubMed DOI
Novotna A, Srovnalova A, Svecarova M, Korhonova M, Bartonkova I, Dvorak Z (2014) Differential Effects of Omeprazole and Lansoprazole Enantiomers on Aryl Hydrocarbon Receptor in Human Hepatocytes and Cell Lines. Plos One 9. PubMed PMC
Novotna A, Dvorak Z (2014) Omeprazole and Lansoprazole Enantiomers Induce CYP3A4 in Human Hepatocytes and Cell Lines via Glucocorticoid Receptor and Pregnane X Receptor Axis. Plos One 9. PubMed PMC
Novotna A, Petr P, Dvorak Z (2011) Novel Stably Transfected Gene Reporter Human Hepatoma Cell Line for Assessment of Aryl Hydrocarbon Receptor Transcriptional Activity: Construction and Characterization. Environmental Science & Technology 45: 10133–10139. PubMed
Novotna A, Pavek P, Dvorak Z (2012) Construction and characterization of a reporter gene cell line for assessment of human glucocorticoid receptor activation. European Journal of Pharmaceutical Sciences 47: 842–847. 10.1016/j.ejps.2012.10.003 PubMed DOI
Vrzal R, Knoppova B, Bachleda P, Dvorak Z (2013) Effects of oral anorexiant sibutramine on the expression of cytochromes P450s in human hepatocytes and cancer cell lines. J Biochem Mol Toxicol 27: 515–521. 10.1002/jbt.21516 PubMed DOI
Vavrova A, Vrzal R, Dvorak Z (2013) A nonradioactive electrophoretic mobility shift assay for measurement of pregnane X receptor binding activity to CYP3A4 response element. Electrophoresis 34: 1863–1868. PubMed
Doricakova A, Novotna A, Vrzal R, Pavek P, Dvorak Z (2013) The role of residues T248, Y249 and T422 in the function of human pregnane X receptor. Arch Toxicol 87: 291–301. 10.1007/s00204-012-0937-9 PubMed DOI
Goodwin B, Hodgson E, Liddle C (1999) The orphan human pregnane X receptor mediates the transcriptional activation of CYP3A4 by rifampicin through a distal enhancer module. Molecular Pharmacology 56: 1329–1339. PubMed
Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998) The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions. Journal of Clinical Investigation 102: 1016–1023. PubMed PMC
Meadowcroft AM, Williamson KM, Patterson JH, Hinderliter AL, Pieper JA (1999) The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers. Journal of Clinical Pharmacology 39: 418–424. PubMed
Sekhar MC, Reddy PJC (2012) Influence of atorvastatin on the pharmacodynamic and pharmacokinetic activity of repaglinide in rats and rabbits. Molecular and Cellular Biochemistry 364: 159–164. 10.1007/s11010-011-1214-6 PubMed DOI
Lee CK, Choi JS, Choi DH (2015) Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of nifedipine in rats: Possible role of P-gp and CYP3A4 inhibition by HMG-CoA reductase inhibitors. Pharmacological Reports 67: 44–51. 10.1016/j.pharep.2014.08.005 PubMed DOI
Choi DH, Shin WG, Choi JS (2008) Drug interaction between oral atorvastatin and verapamil in healthy subjects: effects of atorvastatin on the pharmacokinetics of verapamil and norverapamil. European Journal of Clinical Pharmacology 64: 445–449. 10.1007/s00228-007-0447-5 PubMed DOI
Fischer V, Johanson L, Heitz F, Tullman R, Graham E, Baldeck JP, et al. (1999) The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor fluvastatin: Effect on human cytochrome P-450 and implications for metabolic drug interactions. Drug Metabolism and Disposition 27: 410–416. PubMed
Cohen LH, van Leeuwen RE, van Thiel GC, van Pelt JF, Yap SH (2000) Equally potent inhibitors of cholesterol synthesis in human hepatocytes have distinguishable effects on different cytochrome P450 enzymes. Biopharm Drug Dispos 21: 353–364. PubMed
Transon C, Leemann T, Dayer P (1996) In vitro comparative inhibition profiles of major human drug metabolising cytochrome p450 isozymes (CYP2C9, CYP2D6 and CYP3A4) by HMG-CoA reductase inhibitors. European Journal of Clinical Pharmacology 50: 209–215. PubMed
Boralli VB, Coelho EB, Sampaio SA, Marques MP, Lanchote VL (2009) Enantioselectivity in the Pharmacokinetic Interaction Between Fluvastatin and Lercanidipine in Healthy Volunteers. Journal of Clinical Pharmacology 49: 205–211. 10.1177/0091270008327536 PubMed DOI
Di Pietro G, Coelho EB, Geleilete TM, Marques MP, Lanchote VL (2006) Chiral evaluation of fluvastatin in human plasma by high-performance liquid chromatography electrospray mass spectrometry. Journal of Chromatography B-Analytical Technologies in the Biomedical and Life Sciences 832: 256–261. PubMed
Kobayashi K, Yamanaka Y, Iwazaki N, Nakajo I, Hosokawa M, Negishi M, et al. (2005) Identification of HMG-CoA reductase inhibitors as activators for human, mouse and rat constitutive androstane receptor. Drug Metab Dispos 33: 924–929. PubMed
Pascussi JM, Gerbal-Chaloin S, Duret C, Daujat-Chavanieu M, Vilarem MJ, Maurel P (2008) The tangle of nuclear receptors that controls xenobiotic metabolism and transport: crosstalk and consequences. Annu Rev Pharmacol Toxicol 48: 1–32. PubMed
Garcia I, Fall Y, Gomez G (2012) Review of synthesis, biological assay, and QSAR studies of HMGR inhibitors. Curr Top Med Chem 12: 895–919. PubMed