Drug Metab Drug Interact 2014; 29(4): 207–209
Editorial Gérard Siest*, Sylvie Fournel-Gigleux and Jacques Magdalou
CYP 2C19 and UDP-glucuronosyltransferases not only for drugs but also for endobiotics DOI 10.1515/dmdi-2014-0030
Drug metabolism is under the control of many enzymes, essentially cytochromes P450 (CYP) catalyzing oxidation in phase I and transferases catalyzing the addition of UDPGA or glutathione in phase II. Transporter enzymes (phase III) are part of the system. All these enzymes also transform xenobiotic from our environment, including food constituents. An interesting theory based on the localization of these enzymes in their protective organs is their role against external aggressions (liver, intestine, lung, kidney, and skin). But all these enzymes also have an important role in humans’ overall metabolism and disposition of a wide range of endogenous constituents, including steroid hormones (estrogen and testosterone), vitamin D, cholesterol, and fatty acids. Human UDP-glucuronosyltransferases (UGTs) are also involved in steroid and biliary acid metabolism. All these enzyme families metabolizing drugs and xenobiotics and the endogenous metabolites compete directly for drug targets or regulatory domains of dedicated receptors, particularly the nuclear ones. It is evident that the possibilities of interactions between exogenous and endogenous metabolites are a potential safety problem. We would like to take, as example, CYP2C (CYP2C19) and UGTs for which new roles in human metabolism have been described.
CYP2C and epoxyygenases CYP epoxygenase enzymes play an indispensable role in the regulation of inflammation through the biosynthesis of endogenous bioactive lipid mediators that modulate inflammation, such as arachidonic acid (AA) derivatives and epoxyeicosatrienoic acids (EETs) [1]. AA is a 20-carbon, omega-6 polyunsaturated fatty acid that resides in the cell membrane phospholipids in the stereospecific numbering-2 position and is released
upon stimulation by the cytosolic enzyme phospholipase A2. The free intracellular AA is converted to a series of biological active metabolites by three different pathways, the third one being the eicosanoid enzymatic pathway metabolizing AA to EETs and hydroxyeicosatetraenoic acids (HETEs) by CYP epoxygenases and epoxide hydrolases, respectively [2]. CYP2C8, CYP2C9, CYP2C19, and CYP2J2 isoforms have been identified as the main CYP epoxygenases involved in the biotransformation of AA to EETs in a human with a predominant activity in the liver. These cytochromes p450 also metabolize a large number of drugs [2], which compete with eicosanoids for the same CYP active site [3]. It is then important to check the potential interaction between clopidogrel and inflammatory process [4]. In addition, these CYPs are highly inducible by drugs and environmental compounds after their binding to nuclear receptors [5]. Another recent finding is the implication of CYP 2C19 in brain metabolism and probably in neurological diseases [6]. The interaction with drugs in these organs is of great importance.
UDPGTs UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes that catalyze the binding of glucuronic acid, from the high-energy donor UDP-glucuronic acids on structurally unrelated substances with a functionalized group (hydroxyl, phenyl, carboxylic acid, amine) leading to the formation of water-soluble glucuronides, easily eliminated into bile or urine [7]. In humans, up to 22 UGT isoforms have been identified to date [8]. The hydroxylated products of the CYP reactions are readily glucuronidated. The main characteristics of UGTs is their potency to glucuronidate a large array of substances; among those are pollutants, compounds present in our environment or in the diet, and drugs and other therapeutic substances. The corresponding glucuronides are generally devoid of toxicity or pharmacological activity. As such, UGTs play
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208 Siest et al.: CYP 2C19 and UDP-glucuronosyltransferases a major role as a detoxication barrier, thus protecting the organism against hazardous chemicals [9]. Interestingly, UGTs are also involved in the metabolism of endogenous substances (bilirubin, steroid, thyroid hormones, bile acids, neurotransmitters, etc.) [10]. UGTs are capable of metabolic inactivation of steroids, such as estradiol and androgens in breast tissue or prostate [11, 12]. These studies highlight the potential importance of these enzymes in cancer diseases. UGTs catalyze the glucuronidation of neurotransmitters, such as dopamine and 5-hydroxytryptamine, in human and rat brain [13, 14]. With the sulfotransferases, they play a key role in the homeostasis of these substances. Competition between xenobiotics and endobiotics occurs at two protein target levels, the nuclear receptors and the UGTs themselves. Indeed, most endobiotic substrates of UGTs are ligands of nuclear receptors, such as the peroxisome proliferator-activated receptors (PPARs) [15], and play a key role in cell differentiation and interactions. In that respect, UGTs participate in the modulation of their concentration and biological activity within the cells. In turn, these nuclear receptors are efficient regulators of UGT gene activity, thus indicating that these endobiotics control their own glucuronidation [16]. As previously mentioned for CYP, UGTs are also involved in the glucuronidation of linoleic acid and AA metabolites (leukotriene B4; 5-, 12-, 15-HETE; 13-hydroxyoctadecadienoic acid) that are natural ligands of PPARs [17]. They control the homeostasis of these physiologically important endogenous substances and protect tissues from deleteriously high concentrations. On the other hand, xenobiotics and endogenous substances may compete with each other toward the same UGT isoform. As a consequence, administration of drugs affects the activity of UGT toward endogenous compounds, via inhibition mechanisms of the active site and alters their metabolism. For example, SN38, the active metabolite of the anticancer drug irinotecan, is glucuronidated mainly by the UGT1A1 isoform, which is the only UGT enzyme able to metabolize the toxic compound bilirubin into water-soluble mono- and di-glucuronides [18]. Administration of SN38 has been shown to increase bilirubin levels, leading to adverse effects [19]. On the other hand, the UGT1A1 gene presents a high degree of polymorphism diversity in humans, leading to a reduction in enzyme activity to various extents. In such condition, irinotecan toxicity is increased (diarrhea) in patients with low activity genotypes [20]. Genotyping patients (personalized medicine) treated with the drug allows the determination of the most efficient dose for colorectal cancer treatment. Epigenetic silencing of UGT1A1 by DNA methylation in colon cancer has also been reported to
affect the clinical response of irinotecan [21]. Inhibition of other UGT isoforms can also occur, but with less important consequences since they present an overlapping substrate specificity [22]. Additionally, some of the endobiotics and xenobiotics, especially with a hydroxyl, phenolic, or amine group can also be metabolized by sulfotransferases, which contributes to their elimination [23]. In summary, a better understanding of the UGT structure and function at the gene and protein levels and of the molecular mechanisms of their regulation by the various nuclear receptors may affect new drug development processes. In conclusion, it becomes more and more important to check endiobiotics and drug interactions during the preclinical and clinical trials [24] in order to lead to safer and more efficient therapeutic substances. To develop this recommendation, the European Society of Pharmacogenimics and Theranostics could create a specific committee. Conflict of interest statement Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References 1. Shahabi P, Siest G, Meyer UA, Visvikis-Siest S. Human cytochrome P450 epoxygenase: variability in expression and role in inflammation related disorders. Pharmacol Ther 2014;144:134–61. 2. Shahabi P, Siest G, Visvikis-Siest S. Influence of inflammation on cardiovascular protective effects of cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids. Drug Metab Rev 2014;46:33–56. 3. Yamazaki H, Shimada T. Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by human cytochrome P450 enzymes. Xenobiotica 1999;29:231–41. 4. Shahabi P, Cuisset T, Herbeth B, Morange PE, Grosdidier C, Stathopoulou MG, et al. Genetic-determined low response to thienopyridines is associated with higher systemic inflammation in smokers. Pharmacogenom 2015 (in print). 5. Amacher DE. The effects of cytochrome P450 induction by xenobiotics on endobiotic metabolism in pre-clinical safety studies. Toxicol Mech Methods. 2010;20:159–66.
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Siest et al.: CYP 2C19 and UDP-glucuronosyltransferases 209 6. Ingelman-Sundberg M. Pharmacogenomics of endogenous metabolism and its implication for behavior, psychopatho logy and treatment [abstract]. Drug Metab Drug Interact 2013;28:A1–48. 7. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Bélanger A, et al. The UDP glycosyltransferase gene super family: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 1997;7:255–69. 8. Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol 2013;45:1121–32. 9. Bock KW. Vertebrate UDP-glucuronosyltransferases: functional and evolutionary aspects. Biochem Pharmacol 2003;66:691–6. 10. Bock KW. Homeostatic control of xeno- and endobiotics in the drug-metabolizing enzyme system. Biochem Pharmacol 2014;90:1–6. 11. Guillemette C, Bélanger A, Lépine J. Metabolic activation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview. Breast Cancer Res 2004;6:246–54. 12. Barbier O, Bélanger A. Inactivation of androgens by UDP- glucuronosyltransferases in the human prostate. Best Pract Res Clin Endocrinol Metab 2008;22:259–70. 13. Uutela P, Reinila R, Harju K, Piepponen P, Ketola RA, Kostiainen R. Analysis of intact glucuronides and sulfates of serotonin, dopamine, and their phase I metabolites in rat brain microdialysates by liquid chromatography-tandem mass spectrometry. Anal Chem 2009;81:8417–25. 14. Suominen T, Uutela P, Ketola RA, Bergquist J, Hillered L, Finel M, et al. Determination of serotonin and dopamine metabolites in human brain microdialysis and cerebrospinal fluid samples by UPLC-MS/MS: discovery of intact glucuronide and sulfate conjugates. PLOS One 2013;8:e68007. 15. Grygiel-Gorniak B. Peroxisome proliferator-activated r eceptors and their ligands: nutritional and clinical implications – a review. Nutrition J 2014;13:1–17. 16. Bigo C, Caron S, Dallaire-Théroux A, Barbier O. Nuclear receptors and endobiotics glucuronidation: the good, the bad, and the UGT. Drug Metab Rev 2013;45:34–47.
17. Turgeon D, Chouinard S, Bélanger P, Picard S, Labbé JF, Bourgeat P, et al. Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases. J Lipid Res 2003;44:1182–90. 18. Hanioka N, Ozawa S, Jinno H, Ando M, Saito Y, Sawada J. Human liver UDP-glucuronosyltransferase isoforms involved in the glucuronidation of 7-ethyl-10-hydroxycamptothecin. Xenobiotica 2001;31:687–99. 19. Ramchandani RP, Wang Y, Booth BP, Ibrahim A, Johnson JR, Rahman A, et al. The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol 2007;47:78–86. 20. Li M, Wang Z, Guo J, Liu J, Li C, Liu L, et al. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 2014;7:1653–61. 21. Gagnon JF, Bernard O, Villeneuve L, Têtu B, Guillemette C. Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer. Clin Cancer Res 2006;12:1850–8. 22. Court MH. Isoform-selective probe substrates for in vitro studies of human UDP-glucuronosyltransferases. Methods Enzymol 2005;400:104–16. 23. Wu B, Basu S, Meng S, Wang X, Hu M. Regioselective sulfation and glucuronidation of phenolics: insights into the structural basis. Curr Drug Metab 2011;12:900–16. 24. Knights KM, Rowland A, Miners JO. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 2013;76:587–602.
*Corresponding author: Gérard Siest, University of Lorraine, Cardiovascular Genetics Research Unit, 30 rue Lionnois, Nancy, 54000, France, E-mail: [email protected]; and UMR INSERM U1122 IGE-PCV, Université de Lorraine, Nancy, France Sylvie Fournel-Gigleux and Jacques Magdalou: UMR 7365 CNRSUniversité de Lorraine (Ingénierie Moléculaire Physiopathologie Articulaire), Nancy, France
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Editorial Gérard Siest*, Sylvie Fournel-Gigleux and Jacques Magdalou
CYP 2C19 and UDP-glucuronosyltransferases not only for drugs but also for endobiotics DOI 10.1515/dmdi-2014-0030
Drug metabolism is under the control of many enzymes, essentially cytochromes P450 (CYP) catalyzing oxidation in phase I and transferases catalyzing the addition of UDPGA or glutathione in phase II. Transporter enzymes (phase III) are part of the system. All these enzymes also transform xenobiotic from our environment, including food constituents. An interesting theory based on the localization of these enzymes in their protective organs is their role against external aggressions (liver, intestine, lung, kidney, and skin). But all these enzymes also have an important role in humans’ overall metabolism and disposition of a wide range of endogenous constituents, including steroid hormones (estrogen and testosterone), vitamin D, cholesterol, and fatty acids. Human UDP-glucuronosyltransferases (UGTs) are also involved in steroid and biliary acid metabolism. All these enzyme families metabolizing drugs and xenobiotics and the endogenous metabolites compete directly for drug targets or regulatory domains of dedicated receptors, particularly the nuclear ones. It is evident that the possibilities of interactions between exogenous and endogenous metabolites are a potential safety problem. We would like to take, as example, CYP2C (CYP2C19) and UGTs for which new roles in human metabolism have been described.
CYP2C and epoxyygenases CYP epoxygenase enzymes play an indispensable role in the regulation of inflammation through the biosynthesis of endogenous bioactive lipid mediators that modulate inflammation, such as arachidonic acid (AA) derivatives and epoxyeicosatrienoic acids (EETs) [1]. AA is a 20-carbon, omega-6 polyunsaturated fatty acid that resides in the cell membrane phospholipids in the stereospecific numbering-2 position and is released
upon stimulation by the cytosolic enzyme phospholipase A2. The free intracellular AA is converted to a series of biological active metabolites by three different pathways, the third one being the eicosanoid enzymatic pathway metabolizing AA to EETs and hydroxyeicosatetraenoic acids (HETEs) by CYP epoxygenases and epoxide hydrolases, respectively [2]. CYP2C8, CYP2C9, CYP2C19, and CYP2J2 isoforms have been identified as the main CYP epoxygenases involved in the biotransformation of AA to EETs in a human with a predominant activity in the liver. These cytochromes p450 also metabolize a large number of drugs [2], which compete with eicosanoids for the same CYP active site [3]. It is then important to check the potential interaction between clopidogrel and inflammatory process [4]. In addition, these CYPs are highly inducible by drugs and environmental compounds after their binding to nuclear receptors [5]. Another recent finding is the implication of CYP 2C19 in brain metabolism and probably in neurological diseases [6]. The interaction with drugs in these organs is of great importance.
UDPGTs UDP-glucuronosyltransferases (UGTs) are a multigenic family of enzymes that catalyze the binding of glucuronic acid, from the high-energy donor UDP-glucuronic acids on structurally unrelated substances with a functionalized group (hydroxyl, phenyl, carboxylic acid, amine) leading to the formation of water-soluble glucuronides, easily eliminated into bile or urine [7]. In humans, up to 22 UGT isoforms have been identified to date [8]. The hydroxylated products of the CYP reactions are readily glucuronidated. The main characteristics of UGTs is their potency to glucuronidate a large array of substances; among those are pollutants, compounds present in our environment or in the diet, and drugs and other therapeutic substances. The corresponding glucuronides are generally devoid of toxicity or pharmacological activity. As such, UGTs play
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208 Siest et al.: CYP 2C19 and UDP-glucuronosyltransferases a major role as a detoxication barrier, thus protecting the organism against hazardous chemicals [9]. Interestingly, UGTs are also involved in the metabolism of endogenous substances (bilirubin, steroid, thyroid hormones, bile acids, neurotransmitters, etc.) [10]. UGTs are capable of metabolic inactivation of steroids, such as estradiol and androgens in breast tissue or prostate [11, 12]. These studies highlight the potential importance of these enzymes in cancer diseases. UGTs catalyze the glucuronidation of neurotransmitters, such as dopamine and 5-hydroxytryptamine, in human and rat brain [13, 14]. With the sulfotransferases, they play a key role in the homeostasis of these substances. Competition between xenobiotics and endobiotics occurs at two protein target levels, the nuclear receptors and the UGTs themselves. Indeed, most endobiotic substrates of UGTs are ligands of nuclear receptors, such as the peroxisome proliferator-activated receptors (PPARs) [15], and play a key role in cell differentiation and interactions. In that respect, UGTs participate in the modulation of their concentration and biological activity within the cells. In turn, these nuclear receptors are efficient regulators of UGT gene activity, thus indicating that these endobiotics control their own glucuronidation [16]. As previously mentioned for CYP, UGTs are also involved in the glucuronidation of linoleic acid and AA metabolites (leukotriene B4; 5-, 12-, 15-HETE; 13-hydroxyoctadecadienoic acid) that are natural ligands of PPARs [17]. They control the homeostasis of these physiologically important endogenous substances and protect tissues from deleteriously high concentrations. On the other hand, xenobiotics and endogenous substances may compete with each other toward the same UGT isoform. As a consequence, administration of drugs affects the activity of UGT toward endogenous compounds, via inhibition mechanisms of the active site and alters their metabolism. For example, SN38, the active metabolite of the anticancer drug irinotecan, is glucuronidated mainly by the UGT1A1 isoform, which is the only UGT enzyme able to metabolize the toxic compound bilirubin into water-soluble mono- and di-glucuronides [18]. Administration of SN38 has been shown to increase bilirubin levels, leading to adverse effects [19]. On the other hand, the UGT1A1 gene presents a high degree of polymorphism diversity in humans, leading to a reduction in enzyme activity to various extents. In such condition, irinotecan toxicity is increased (diarrhea) in patients with low activity genotypes [20]. Genotyping patients (personalized medicine) treated with the drug allows the determination of the most efficient dose for colorectal cancer treatment. Epigenetic silencing of UGT1A1 by DNA methylation in colon cancer has also been reported to
affect the clinical response of irinotecan [21]. Inhibition of other UGT isoforms can also occur, but with less important consequences since they present an overlapping substrate specificity [22]. Additionally, some of the endobiotics and xenobiotics, especially with a hydroxyl, phenolic, or amine group can also be metabolized by sulfotransferases, which contributes to their elimination [23]. In summary, a better understanding of the UGT structure and function at the gene and protein levels and of the molecular mechanisms of their regulation by the various nuclear receptors may affect new drug development processes. In conclusion, it becomes more and more important to check endiobiotics and drug interactions during the preclinical and clinical trials [24] in order to lead to safer and more efficient therapeutic substances. To develop this recommendation, the European Society of Pharmacogenimics and Theranostics could create a specific committee. Conflict of interest statement Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References 1. Shahabi P, Siest G, Meyer UA, Visvikis-Siest S. Human cytochrome P450 epoxygenase: variability in expression and role in inflammation related disorders. Pharmacol Ther 2014;144:134–61. 2. Shahabi P, Siest G, Visvikis-Siest S. Influence of inflammation on cardiovascular protective effects of cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids. Drug Metab Rev 2014;46:33–56. 3. Yamazaki H, Shimada T. Effects of arachidonic acid, prostaglandins, retinol, retinoic acid and cholecalciferol on xenobiotic oxidations catalysed by human cytochrome P450 enzymes. Xenobiotica 1999;29:231–41. 4. Shahabi P, Cuisset T, Herbeth B, Morange PE, Grosdidier C, Stathopoulou MG, et al. Genetic-determined low response to thienopyridines is associated with higher systemic inflammation in smokers. Pharmacogenom 2015 (in print). 5. Amacher DE. The effects of cytochrome P450 induction by xenobiotics on endobiotic metabolism in pre-clinical safety studies. Toxicol Mech Methods. 2010;20:159–66.
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Siest et al.: CYP 2C19 and UDP-glucuronosyltransferases 209 6. Ingelman-Sundberg M. Pharmacogenomics of endogenous metabolism and its implication for behavior, psychopatho logy and treatment [abstract]. Drug Metab Drug Interact 2013;28:A1–48. 7. Mackenzie PI, Owens IS, Burchell B, Bock KW, Bairoch A, Bélanger A, et al. The UDP glycosyltransferase gene super family: recommended nomenclature update based on evolutionary divergence. Pharmacogenetics 1997;7:255–69. 8. Rowland A, Miners JO, Mackenzie PI. The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol 2013;45:1121–32. 9. Bock KW. Vertebrate UDP-glucuronosyltransferases: functional and evolutionary aspects. Biochem Pharmacol 2003;66:691–6. 10. Bock KW. Homeostatic control of xeno- and endobiotics in the drug-metabolizing enzyme system. Biochem Pharmacol 2014;90:1–6. 11. Guillemette C, Bélanger A, Lépine J. Metabolic activation of estrogens in breast tissue by UDP-glucuronosyltransferase enzymes: an overview. Breast Cancer Res 2004;6:246–54. 12. Barbier O, Bélanger A. Inactivation of androgens by UDP- glucuronosyltransferases in the human prostate. Best Pract Res Clin Endocrinol Metab 2008;22:259–70. 13. Uutela P, Reinila R, Harju K, Piepponen P, Ketola RA, Kostiainen R. Analysis of intact glucuronides and sulfates of serotonin, dopamine, and their phase I metabolites in rat brain microdialysates by liquid chromatography-tandem mass spectrometry. Anal Chem 2009;81:8417–25. 14. Suominen T, Uutela P, Ketola RA, Bergquist J, Hillered L, Finel M, et al. Determination of serotonin and dopamine metabolites in human brain microdialysis and cerebrospinal fluid samples by UPLC-MS/MS: discovery of intact glucuronide and sulfate conjugates. PLOS One 2013;8:e68007. 15. Grygiel-Gorniak B. Peroxisome proliferator-activated r eceptors and their ligands: nutritional and clinical implications – a review. Nutrition J 2014;13:1–17. 16. Bigo C, Caron S, Dallaire-Théroux A, Barbier O. Nuclear receptors and endobiotics glucuronidation: the good, the bad, and the UGT. Drug Metab Rev 2013;45:34–47.
17. Turgeon D, Chouinard S, Bélanger P, Picard S, Labbé JF, Bourgeat P, et al. Glucuronidation of arachidonic and linoleic acid metabolites by human UDP-glucuronosyltransferases. J Lipid Res 2003;44:1182–90. 18. Hanioka N, Ozawa S, Jinno H, Ando M, Saito Y, Sawada J. Human liver UDP-glucuronosyltransferase isoforms involved in the glucuronidation of 7-ethyl-10-hydroxycamptothecin. Xenobiotica 2001;31:687–99. 19. Ramchandani RP, Wang Y, Booth BP, Ibrahim A, Johnson JR, Rahman A, et al. The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity. J Clin Pharmacol 2007;47:78–86. 20. Li M, Wang Z, Guo J, Liu J, Li C, Liu L, et al. Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 2014;7:1653–61. 21. Gagnon JF, Bernard O, Villeneuve L, Têtu B, Guillemette C. Irinotecan inactivation is modulated by epigenetic silencing of UGT1A1 in colon cancer. Clin Cancer Res 2006;12:1850–8. 22. Court MH. Isoform-selective probe substrates for in vitro studies of human UDP-glucuronosyltransferases. Methods Enzymol 2005;400:104–16. 23. Wu B, Basu S, Meng S, Wang X, Hu M. Regioselective sulfation and glucuronidation of phenolics: insights into the structural basis. Curr Drug Metab 2011;12:900–16. 24. Knights KM, Rowland A, Miners JO. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 2013;76:587–602.
*Corresponding author: Gérard Siest, University of Lorraine, Cardiovascular Genetics Research Unit, 30 rue Lionnois, Nancy, 54000, France, E-mail: [email protected]; and UMR INSERM U1122 IGE-PCV, Université de Lorraine, Nancy, France Sylvie Fournel-Gigleux and Jacques Magdalou: UMR 7365 CNRSUniversité de Lorraine (Ingénierie Moléculaire Physiopathologie Articulaire), Nancy, France
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