Abstract
Background
The compound 9-(2′-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), the promising antitumor agent developed in our laboratory was determined to undergo phase I metabolic pathways. The present studies aimed to know its biotransformation with phase II enzymes — UDP-glucuronosyltransferases (UGTs) and its potential to be engaged in drug-drug interactions arising from the modulation of UGT activity.
Methods
UGT-mediated transformations with rat liver (RLM), human liver (HLM), and human intestine (HIM) microsomes and with 10 recombinant human isoenzymes were investigated. Studies on the ability of C-1748 to inhibit UGT were performed with HLM, HT29 colorectal cancer cell homogenate and the selected recombinant UGT isoenzymes. The reactions were monitored using HPLC-UV/Vis method and the C-1748 metabolite structure was determined with ESI-TOF-MS/MS analysis.
Results
Pseudo-molecular ion (m/z 474.1554) and the experiment with β-glucuronidase indicated that O-glucuronide of C-1748 was formed in the presence of microsomal fractions. This reaction was selectively catalyzed by UGT2B7 and 2B17. High inhibitory effect of C-1748 was shown towards isoenzyme UGT1A9 (IC50 = 39.7 μM) and significant but low inhibitory potential was expressed in HT29 cell homogenate (IC50 = 84.5 μM). The mixed-type inhibition mechanism (Ki = 17.0 μM; Ki ‘= 81.0 μM), induced by C-1748 was observed for recombinant UGT1A9 glucuronidation, whereas HT29 cell homogenate resulted in noncompetitive inhibition (Ki = 94.6 μM).
Conclusions
The observed UGT-mediated metabolism of C-1748 and its ability to inhibit UGT activity should be considered as the potency for drug resistance and drug-drug interactions in the prospective multidrug therapy.
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References
Guillmette C.. Pharmacogenomics of human UDP-glucuronosyltransferase enzymes. Xenobiotica 2003;3:136–58.
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.
Miners JO, Mackenzie PI, Knights KM. The prediction of drug glucuronidation parameters in humans: UDP-glucuronosyltransferase enzyme selective substrate and inhibitor probes for reaction phenotyping and in vitro-in vivo extrapolation of drug clearance and DDIs potential. Drug Metab Rev 2010;42:196–208.
Kiang TKL, Ensom MHH, Chang TKH. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacol Ther 2005;106:97–132.
Gan J, Chen W, Shen H, Gao L, Hong Y, Tian Y, et al. Rapaglinide-gemfibrozil drug interaction: inhibition of rapaglinide glucuronidation as a potential additional contributing mechanism. Br J Clin Pharmacol 2010;70:870–80.
Gaganis P, Miners JO, Knights KM. Glucuronidation of fenamates: kinetic studies using human kidney cortical microsomes and recombinant UDP-glucuronosyltransferase (UGT) 1A9 and 2B7. Biochem Pharmacol 2007;73:1683–91.
Miners JO, Bowalgaha K, Elliot DJ, Baranczewski P. Characterization of niflumic acid as a selective inhibitor of human liver micarosomal UDP-glucuronosyltransferase 1A9: application to the reaction phenotyping of acetaminophen glucuronidation. Drug Metab Dispos 2011;39:644–52.
Liu Y, Ramírez J, House L, Ratain MJ. Comparison of the drug-drug interactions potential of erlotinib and gefitinib via inhibition of UDP-glucuronosyltransferases. Drug Metab Dispos 2010;38:32–9.
Mross K, Steinbild S, Baas F, Gmehling D, Radtke M, Voliotis D, et al. Results from an in vitro and clinical/pharmacological phase I study with combination irinotecan and sorafenib. Eur J Cancer 2007;43:55–63.
Miners JO, Chau N, Rowland A, Burns K, McKinnon RA, Mackenzie PI, et al. Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: implications for hyperbilirubinemia. Biochem Pharmacol 2017;129:85–95.
Xin H, Qi XY, Wu JJ, Wang XX, Li Y, Hong JY, et al. Assessment of the inhibition potential of Licochalcone A against human UDP-glucuronosyltransferases. Food Chem Toxicol 2016;90:112–22.
Ma HY, Sun DX, Cao YF, Ai CZ, Qu YQ, Hu CM, et al. Herb-drug interaction prediction based on the high specific inhibition of andrographolide derivatives towards UDP-glucuronosyltransferase (UGT) 2B7. Toxicol Appl Pharmacol 2014;277:86–94.
Kim D, Zheng YF, Min JS, Park JB, Bae SH, Yoon KD, et al. In vitro stereoselective inhibition of ginsenosides toward UDP-glucuronosyltransferase (UGT) isoforms. Toxicol Lett 2016;259:1–10.
Augustin E, Moś-Rompa A, Nowak-Ziatyk D, Konopa J. Antitumor 1-nitroacridine derivative C-1748, induces apoptosis, necrosis or senescence in human colon carcinoma HCT8 and HT29 cells. Biochem Pharmacol 2010;79:1231–41.
Tadi K, Ashok BT, Chen Y, Banerjee D, Wysocka-Skrzela B, Konopa J, et al. Pre-clinical evaluation of 1-nitroacridine derived chemotherapeutic agent that has preferential cytotoxic activity towards prostate cancer. Cancer Biol Ther 2007;6:1632–7.
Ashok BT, Tadi K, Banerjee D, Konopa J, Iatropoulos M, Tiwari RK. Pre-clinical toxicology and pathology of 9-(2′-hydroxyethylamino)-4-methyl-1-nitroacridine (C-1748), a novel anti-cancer agent in male Beagle dogs. Life Sci 2006;79:1334–42.
Ashok BT, Tadi K, Garikapaty VP, Chen Y, Huang Q, Banerjee D, et al. Preclinical toxicological examination of a putative prostate cancer-specific 4-methyl-1-nitroacridine derivative in rodents. Anticancer Drugs 2007;18:87–94.
Wiśniewska A, Niemira M, Jagiełło K, Potęga A, Swist M, Henderson C, et al. Diminished toxicity of C-1748, 4-methyl-9-hydroxyethylamino-1-nitroacridine, compared with its demethyl analog, C-857, corresponds to its resistance to metabolism in HepG2 cells. Biochem Pharmacol 2012;84:30–42.
Borowa-Mazgaj B, Mróz A, Augustin E, Paluszkiewicz E, Mazerska Z. The overexpression of CPR and P450 3A4 in pancreatic cancer cells changes the metabolic profile and increases the cytotoxicity and pro-apoptotic activity of acridine antitumor agent, C-1748. Biochem Pharmacol 2017;142:21–38.
J. Konopa, B. Wysocka-Skrzela, R.K. Tiwari. 9-Alkilamino-1-nitroacridine derivatives, European patent, 01910914.9-2101-US0105199, American patent, 1981.
Potęga A, Fedejko-Kap B, Mazerska Z. Mechanism-based inactivation of human cytochrome P450 1A2 and 3A4 isoenzymes by anti-tumor triazoloacridinone C-1305. Xenobiotica 2016;46:1056–65.
Cummings J, Ethell BT, Jardine L, Boyd G, Macpherson JS, Burchell B, et al. Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives. Cancer Res 2003;63:8443–50.
Lippert TH, Ruoff HJ, Volm M. Intrinsic and acquired drug resistance in malignant tumors: the main reason for therapeutic failure. Arzneimittelforschung 2008;58:261–4.
Mazerska Z, Mróz A, Pawłowska M, Augustin E. The role of glucuronidation in drug resistance. Pharmacol Ther 2016;159:35–55.
Court MH, Zhang X, Ding X, Yee KK, Hesse LM, Finel M. Quantitative distribution of mRNAs encoding the 19 human UDP-glucuronosyltransferase enzymes in 26 adult and 3 fetal tissues. Xenobiotica 2012;42:266–77.
Parkinson A, Ogilvie BW, Paris BL, Hensley TN, Loewen GJ. Human biotransformation. In: Nasar AF, editor. Biotransformation and Metabolite Elucidation of Xenobiotics. Hoboken, New Jersey: John Wiley & Sons, Inc; 2010.
Dates CR, Fahmi T, Pyrek SJ, Yao-Borengasser A, Borowa-Mazgaj B, Bratton SM, et al. Human UDP-glucuronosyltransferases: effects of altered expression in breast and pancreatic cancer cell lines. Cancer Biol Ther 2015;16:714–23.
Joo J, Kim YW, Wu Z, Shin JH, Lee B, Shon JC, et al. Screening of non-steroidal anti-inflammatory drugs for inhibitory effects on the activities of six UDPglucuronosyltransferases (UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) using LC-MS/MS. Biopharm Drug Dispos 2015;36:258–64.
Zhang N, Liu Y, Jeong H. Drug-Drug interaction potentials of tyrosine kinase inhibitors via inhibition of UDP-glucuronosyltransferases. Sci Rep 2015;5:17778.
Court MH. Isoform-selective probe substrates for in vitro studies of human UDP-glucuronosyltransferases. Methods Enzymol 2005;400:104–16.
Court MH, Duan SX, von Moltke LL, Greenblatt DJ, Patten CJ, Miners JO, et al. Interindividual variability in acetaminophen glucuronidation by human liver microsomes: identification of relevant acetaminophen UDP-glucuronosyltransferase isoforms. J Pharmacol Exp Ther 2001;299:998–1006.
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.
Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos 2004;32:120–8.
Innocenti F, Iyer L, Ramírez J, Green MD, Ratain MJ. Epirubicin glucuronidation is catalyzed by human UDP-glucuronosyltransferase 2B7. Drug Metab Dispos 2001;29:686–92.
Coffman BL, King CD, Rios GR, Tephly TR. The glucuronidation of opioids, other xenobiotics, and androgens by human UGT2B7Y(268) and UGT2B7H(268). Drug Metab Dispos 1998;26:73–7.
Barbier O, Turgeon D, Girard C, Green MD, Tephly TR, Hum DW, Bélanger A. 3′-azido-3′-deoxythimidine (AZT) is glucuronidated by human UDP-glucuronosyltransferase 2B7 (UGT2B7). Drug Metab Dispos 2000;28:497–502.
Margaillan G, Rouleau M, Fallon JK, Caron P, Villeneuve L, Turcotte V. et al: quantitative profiling of human renal UDP-glucuronosyltransferases and glucuronidation activity: a comparison of normal and tumoral kidney tissues. Drug Metab Dispos 2015;43:611–9.
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Mróz, A., Ryska, I., Sominko, H. et al. Drug-drug interaction potential of antitumor acridine agent C-1748: The substrate of UDP-glucuronosyltransferases 2B7, 2B17 and the inhibitor of 1A9 and 2B7. Pharmacol. Rep 70, 972–980 (2018). https://doi.org/10.1016/j.pharep.2018.03.007
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DOI: https://doi.org/10.1016/j.pharep.2018.03.007