Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

Foti, R.; Diaz, Philippe; Douguet, Dominique

doi:10.1080/14756366.2016.1193734

Cited by 11 publications

(14 citation statements)

References 102 publications

(147 reference statements)

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“…9, C and D). However, the IC 50 values, 124 mM (26-594; 95% confidence intervals) with ketoconazole and 3.8 mM (1.8-8.1; 95% CI) with talarozole, were much higher than the IC 50 values observed with CYP26A1 (,10 nM for talarozole and 0.55 mM for ketoconazole) and CYP26B1 (,10 nM for talarozole and 0.59 mM for ketoconazole) (Thatcher et al, 2011;Diaz et al, 2016;Foti et al, 2016a).…”

Section: Cyp26c1 As a Retinoid Hydroxylasementioning

confidence: 70%

CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins

et al. 2018

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The clearance of retinoic acid (RA) and its metabolites is believed to be regulated by the CYP26 enzymes, but the specific roles of CYP26A1, CYP26B1, and CYP26C1 in clearing active vitamin A metabolites have not been defined. The goal of this study was to establish the substrate specificity of CYP26C1, and determine whether CYP26C1 interacts with cellular retinoic acid binding proteins (CRABPs). CYP26C1 was found to effectively metabolize all- retinoic acid (RA), 9--retinoic acid (9--RA), 13--retinoic acid, and 4-oxo-RA with the highest intrinsic clearance toward 9--RA. In comparison with CYP26A1 and CYP26B1, CYP26C1 resulted in a different metabolite profile for retinoids, suggesting differences in the active-site structure of CYP26C1 compared with other CYP26s. Homology modeling of CYP26C1 suggested that this is attributable to the distinct binding orientation of retinoids within the CYP26C1 active site. In comparison with other CYP26 family members, CYP26C1 was up to 10-fold more efficient in clearing 4-oxo-RA (intrinsic clearance 153 l/min/pmol) than CYP26A1 and CYP26B1, suggesting that CYP26C1 may be important in clearing this active retinoid. In support of this, CRABPs delivered 4-oxo-RA and RA for metabolism by CYP26C1. Despite the tight binding of 4-oxo-RA and RA with CRABPs, the apparent Michaelis-Menten constant in biological matrix () value of these substrates with CYP26C1 was not increased when the substrates were bound with CRABPs, in contrast to what is predicted by free drug hypothesis. Together these findings suggest that CYP26C1 is a 4-oxo-RA hydroxylase and may be important in regulating the concentrations of this active retinoid in human tissues.

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Section: Cyp26c1 As a Retinoid Hydroxylasementioning

confidence: 70%

CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins

et al. 2018

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“…This opens the possibility that CYP26B1 may have other substrates. Such a speculation is strengthened by the likely differences in active sites of the two enzymes, revealed by their different responses to various selective inhibitors [38].…”

Section: Discussionmentioning

confidence: 99%

Divergent Roles of CYP26B1 and Endogenous Retinoic Acid in Mouse Fetal Gonads

et al. 2019

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In female mammals, germ cells enter meiosis in the fetal ovaries, while in males, meiosis is prevented until postnatal development. Retinoic acid (RA) is considered the main inducer of meiotic entry, as it stimulates Stra8 which is required for the mitotic/meiotic switch. In fetal testes, the RA-degrading enzyme CYP26B1 prevents meiosis initiation. However, the role of endogenous RA in female meiosis entry has never been demonstrated in vivo. In this study, we demonstrate that some effects of RA in mouse fetal gonads are not recapitulated by the invalidation or up-regulation of CYP26B1. In organ culture of fetal testes, RA stimulates testosterone production and inhibits Sertoli cell proliferation. In the ovaries, short-term inhibition of RA-signaling does not decrease Stra8 expression. We develop a gain-of-function model to express CYP26A1 or CYP26B1. Only CYP26B1 fully prevents STRA8 induction in female germ cells, confirming its role as part of the meiotic prevention machinery. CYP26A1, a very potent RA degrading enzyme, does not impair the formation of STRA8-positive cells, but decreases Stra8 transcription. Collectively, our data reveal that CYP26B1 has other activities apart from metabolizing RA in fetal gonads and suggest a role of endogenous RA in amplifying Stra8, rather than being the initial inducer of Stra8. These findings should reactivate the quest to identify meiotic preventing or inducing substances.

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“…1). Foti et al (2016) reported that the degradation of candesartan cilexetil was minimal upon incubation with CYP2C8, with no appreciable formation of an ester-hydrolyzed product. Computational docking simulation showed that candesartan cilexetil strongly inhibited the CYP2C8-mediated amodiaquine metabolism (IC 50 = 0.50 µM; Walsky et al, 2005), without interacting with the heme.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-β-D-glucuronide in the Liver

et al. 2021

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Growing evidence suggests that certain glucuronides function as potent inhibitors of cytochrome P450 (CYP) 2C8. We previously reported the possibility of drug-drug interactions between candesartan cilexetil and paclitaxel. In this study, we evaluated the effects of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide on pathways associated with the elimination of paclitaxel, including those involving organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, CYP2C8, and CYP3A4. UDP-glucuronosyltransferase (UGT) 1A10 and UGT2B7 were found to increase candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide formation in a candesartan concentration-dependent manner. Additionally, the uptake of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide by cells stably expressing OATPs is a saturable process with a K m of 5.11 and 12.1 μM for OATP1B1 and 28.8 and 15.7 μM for OATP1B3, respectively; both glucuronides exhibit moderate inhibition of OATP1B1/1B3. Moreover, the hydroxylation of paclitaxel was evaluated using recombinant CYP3A4 and CYP3A5. Results show that candesartan, candesartan N2-glucuronide, and candesartan acyl-β-D-glucuronide inhibit the CYP2C8-mediated metabolism of paclitaxel, with candesartan acyl-β-D-glucuronide exhibiting the strongest inhibition (the 50% inhibitory concentration (IC 50 ) is 18.9 µM for candesartan acyl-β-D-glucuronide, 150 µM for candesartan, and 166 µM for candesartan N2-glucuronide). However, time-dependent inhibition of CYP2C8 by candesartan acyl-β-D-glucuronide was not observed. Conversely, the IC 50 values of all the compounds are comparable for CYP3A4. Taken together, these data suggest that candesartan acyl-β-D-glucuronide is actively transported by OATPs into hepatocytes, and drug-drug interactions may occur with coadministration of candesartan and CYP2C8 substrates including paclitaxel as a result of the inhibition of CYP2C8 function.

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Comparison of the ligand binding site of CYP2C8 with CYP26A1 and CYP26B1: a structural basis for the identification of new inhibitors of the retinoic acid hydroxylases

Cited by 11 publications

References 102 publications

CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins

CYP26C1 Is a Hydroxylase of Multiple Active Retinoids and Interacts with Cellular Retinoic Acid Binding Proteins

Divergent Roles of CYP26B1 and Endogenous Retinoic Acid in Mouse Fetal Gonads

In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-β-D-glucuronide in the Liver

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