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Di Paolo, Veronica (2019) Caratterizzazione in vitro della biotrasformazione di nuovi potenziali farmaci per la terapia dei tumori. [Ph.D. thesis]

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Abstract (italian or english)

La caratterizzazione della stabilità metabolica di un nuovo potenziale farmaco e l’identificazione del sistema enzimatico coinvolto nella sua biotrasformazione rivestono notevole importanza nello sviluppo di nuovi agenti terapeutici [Foti e Dalvie, Drug Metab Dispos, 44:1229, 2016]. Un primo obiettivo dell’attività svolta nell’ambito del Dottorato di Ricerca era rappresentato dalla valutazione della reattività nei confronti del tripeptide glutatione (GSH) di alcuni derivati del nitrobenzossadiazolo in fase di caratterizzazione preclinica, quali agenti antitumorali, rappresentati dall’inibitore di GSTP1-1 6-(7-nitro-2,1,3-benzossadiazol-4-iltio)esanolo (NBDHEX) e dai suoi analoghi MC3181, MC2753.
I risultati ottenuti dimostrano come l’estere benzoico di NBDHEX (MC2753) presenti, a differenza di NBDHEX e MC3181, elevata stabilità in presenza di concentrazioni fisiologiche di GSH [Fulci et al., J Enzyme Inhib Med Chem, 32:240, 2017]. Successivi esperimenti, volti a valutare la stabilità di MC2753 all’azione di esterasi, hanno tuttavia dimostrato un’elevata suscettibilità del composto all’idrolisi mediata da carbossilesterasi (CES) microsomiali epatiche umane. La sostituzione della funzione esterea presente in MC2753 con una funzione ammidica ha permesso l’ottenimento di un composto (MC4351) molto promettente, in quanto dotato di stabilità all’azione di CES microsomiali e, a differenza di NBDHEX e MC3181, scarsamente reattivo vs. GSH.
Alla luce di un possibile riposizionamento in ambito oncologico della pirimetamina (PYR) [Fang, Cancers (Basel), 6:494, 2014], sostanza nota per la sua attività antiprotozoaria, è stato inoltre intrapreso uno studio con l’obiettivo di ampliare le conoscenze sul suo destino metabolico. Studi di metabolismo epatico in vitro, condotti al fine di valutare la possibile glucuronidazione e/o ossidazione del farmaco in presenza di frazioni microsomiali umane e di ratto, hanno dimostrato come esso non vada incontro a glucuronidazione nelle due specie considerate. Per contro, l’incubazione di PYR con adenina dinucleotide fosfato ridotto (NADPH) e microsomi epatici di ratto, o microsomi epatici umani isolati da un soggetto trattato con fenobarbital, ha condotto alla formazione di almeno 3 prodotti di mono-ossigenazione, rilevati grazie ad analisi in cromatografia liquida accoppiata a rivelatore spettrofotometrico a serie di diodi e spettrometria di massa (LC-DAD-MS).
È stato esaminato, inoltre, il metabolismo microsomiale epatico di una piccola batteria (n=6) di nuovi inibitori della polimerizzazione della tubulina, derivati del 7-fenilpirrolochinolinone (7-PPyQ). Particolarmente interessanti, in virtù della stabilità dimostrata in presenza di microsomi epatici umani sia in assenza (metabolismo idrolitico) sia in presenza di NADPH (metabolismo ossidativo), sono risultati gli N-benzoil derivati del 7-PPyQ denominati MG2718 e MG2854. Entrambi i composti sono attualmente in fase di screening per l’attività antineoplastica.
Un ulteriore obiettivo dell’attività svolta nell’ambito del Dottorato di Ricerca riguardava la comparazione nelle specie uomo, ratto e topo della stabilità al metabolismo ossidativo citosolico epatico di una piccola batteria di aldeidi aromatiche, rappresentate dall’o-vanillina, un inibitore di NFkB dotato di significativa attività antitumorale [Marton et al., Anticancer Res, 36:5743, 2016] e alcuni suoi analoghi strutturali. Gli stessi composti sono in fase di screening per l’attività antineoplastica presso il Biological Research Centre (BRC) dell’Accademia delle Scienze Ungheresi di Szeged e il Dipartimento di Scienze del Farmaco dell’Università di Padova. Il progetto ha la finalità di identificare composti con attività biologica sovrapponibile o superiore all’o-vanillina e caratterizzati, al tempo stesso, da più elevata stabilità metabolica. I risultati sino ad ora ottenuti indicano un significativo coinvolgimento di aldeidi ossidasi (AOX) murine nel metabolismo citosolico di tutte le aldeidi aromatiche studiate e l’esistenza di profonde differenze interspecie tra l’uomo e il topo nel metabolismo di questi composti.
Infine, in collaborazione con il Centro Ricerche Aptuit di Verona e la Molecular Modeling Section del DSF dell’Università di Padova è stato avviato un progetto con l’obiettivo di identificare inibitori selettivi di solfotrasferasi (SULT) umane che consentano l’esecuzione di studi di fenotipizzazione di reazione. Ad oggi, infatti non vi è la disponibilità di un panel completo di inibitori selettivi verso singole SULT. Gli studi sino ad ora condotti hanno portato all’identificazione di due potenti inibitori delle principali SULT epatiche coinvolte nel metabolismo degli xenobiotici ossia SULT1A1 e SULT1B1

Abstract (a different language)

Drug metabolism studies play an important role in drug discovery and development [Foti and Dalvie, Drug Metab Dispos, 44: 1229, 2016]. A first aim of this work was to evaluate the reactivity of some nitrobenzoxadiazole (NBD) derivatives, namely the experimental antitumor agent 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) and its analogues MC3181 and MC2753, towards the tripeptide glutathione (GSH).
The obtained results showed that, differently from NBDHEX and MC3181, the benzoic acid ester of NBDHEX (MC2753), was stable in the presence of a physiological concentration of GSH [Fulci et al., J Enzyme Inhib Med Chem, 32: 240, 2017]. Subsequent experiments, aimed at assessing the stability of MC2753 to esterases, demonstrated its high susceptibility to hydrolysis catalyzed by a human liver microsomal carboxylesterase(s). Substitution of the ester group of MC2753 with an amide group gave compound MC4351, which was stable in the presence of human liver microsomes (HLMs), and quite less reactive than NBDHEX and MC3181 towards GSH.
In the perspective of a possible repositioning of the antiprotozoal drug pyrimethamine (PYR) in the oncological field [Fang, Cancers (Basel), 6:494, 2014], a study was undertaken to improve the knowledge on its metabolic fate. In vitro studies were therefore conducted to investigate the possible oxidation and/or glucuronidation of PYR by HLMs or rat liver microsomes (RLMs). PYR was found to be stable in the presence of uridine 5'-diphospho-glucuronic acid (UDPGA)-supplemented HLMs or RLMs. On the other hand, PYR underwent NADPH-dependent metabolism by phenobarbital-induced RLMs, as well as by HLMs from a subject receiving phenobarbital; liquid chromatograpy coupled to diode array detection and mass spectrometry (LC-DAD-MS) analysis indicated formation of at least three monoxygenated metabolites.
In vitro microsomal stability experiments were also conducted on a small panel of derivatives of the experimental tubulin polymerization inhibitor 7-phenylpyrroloquinolinone (7-PPyQ). Among the studied compounds, the N-benzoyl derivatives of 7-PPyQ named MG2718 and MG2854 are of considerable interest, due to their stability in HLMs both in the absence (hydrolytic metabolism) and in the presence of NADPH (oxidative metabolism). Both compounds are currently being screened for antineoplastic activity.
Further trials analyzed the liver cytosolic stability of a small panel of aromatic aldehydes including o-vanillin, an inhibitor of NFkB with significant antitumor activity [Marton et al., Anticancer Res, 36: 5743, 2016], and some of its structural analogues. The same compounds are currently being screened for antitumor activity at the Biological Research Center (BRC) of the Hungarian Academy of Sciences (Szeged), and at the Department of Pharmaceutical Sciences (DSF) of Padua University. The aim of the project is to identify o-vanillin analogues endowed with a better pharmacological profile, in terms of both anticancer efficacy and metabolic stability. The results obtained indicate a significant involvement of a murine aldehyde oxidase(s) (AOX) in the metabolism of all the studied aldehydes, and the existence of remarkable differences between human and mouse in the rate of liver cytosolic metabolism of these compounds.
Finally, a collaborative project has been recently established with the Aptuit Research Center in Verona and the Molecular Modeling Section of the DSF of Padua University, to identify form-selective inhibitors of the main human sulfotransferases (SULTs) involved in drug metabolism. The studies have led to the identification of two potent inhibitors of two major hepatic SULTs, namely SULT1A1 and SULT1B1.

EPrint type:Ph.D. thesis
Tutor:Quintieri, Luigi
Ph.D. course:Ciclo 31 > Corsi 31 > SCIENZE FARMACOLOGICHE
Data di deposito della tesi:29 May 2019
Anno di Pubblicazione:29 May 2019
Key Words:Biotrasformazione, xenobiotici, drug metabolism
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/14 Farmacologia
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze del Farmaco
Codice ID:11957
Depositato il:06 Nov 2019 08:49
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Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

• Adjei A.A., Hidalgo M. Intracellular signal transduction pathway proteins as targets for cancer therapy, J Clin Oncol. 2005; 23:5386-403. Cerca con Google

• Adler V., Yin Z., Fuchs S.Y., Benezra M., Rosario L., Tew K.D., Pincus M.R., Sardana M., Henderson C.J., Wolf C.R., Davis R.J., Ronai Z. Regulation of JNK signaling by GSTp, EMBO J. 1999; 18:1321-34. Cerca con Google

• Agarwal V., Kommaddi R.P., Valli K., Ryoler D., Hyde T.M., Kleinman J.E., Strobel H.W., Ravindranath V. Drug metabolism in human brain: high levels of cytochrome P4503A43 in brain and metabolism of anti-anxiety drug alprazolam to its active metabolite, PloS One, 2008; 3:e2337. Cerca con Google

• Agrawal A.K., Shapiro B.H. Intrinsic signals in the sexually dimorphic circulating growth hormone profiles of the rat, Mol Cell Endocrinol, 2001; 173:167-81. Cerca con Google

• Aliya S., Reddanna P., Thyagaraju K. Does glutathione S-transferase Pi (GST-Pi) a marker protein for cancer?, Mol Cell Biochem. 2003; 253:319-27. Cerca con Google

• Allocati N., Masulli M., Di Ilio C., Federici L. Glutathione transferases: substrates, inihibitors and pro-drugs in cancer and neurodegenerative diseases, Oncogenesis. 2018; 7:8. Cerca con Google

• Alnouti Y., Klaassen C.D. Tissue distribution, ontogeny, and regulation of aldehyde dehydrogenase (Aldh) enzymes mRNA by prototypical microsomal enzyme inducers in mice, Toxicol Sci. 2008; 101:51-64. Cerca con Google

• Amiri K.I., Richmond A. Role of nuclear factor-kappa B in melanoma, Cancer Metastasis Rev. 2005; 24:301-13. Cerca con Google

• Anuradha K., Shyamala B.N., Naidu M.M. Vanilla--its science of cultivation, curing, chemistry, and nutraceutical properties, Crit Rev Food Sci Nutr. 2013; 53:1250-76. Cerca con Google

• Arora V.K., Philip T., Huang S., Shu Y.Z., A novel ring oxidation of 4- or 5-substituted 2H-oxazole to corresponding 2-oxazolone catalysed by cytosolic aldehyde oxidase, Drug Metab Dispos, 2012; 40:1668-1676. Cerca con Google

• Ascione A., Cianfriglia M., Dupuis M.L., Mallano A., Sau A., Pellizzari Tregno F., Pezzola S., Caccuri A.M. The glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol overcomes the MDR1-P-glycoprotein and MRP1-mediated multidrug resistance in acute myeloid leukemia cells, Cancer Chemother Pharmacol. 2009; 64:419-24. Cerca con Google

• Becker W.M., Hardin J., Kleinsmith L.J., Bertoni G., The Endomembrane System and Peroxisomes In: Becker’s World of the Cell; 2011 Edited by Pearson Benjamin Cummings. Cerca con Google

• Bezerra D.P., Soares A.K., de Sousa D.P. Overview of the Role of Vanillin on Redox Status and Cancer Development, Oxid Med Cell Longev. 2016; 2016:9734816. Cerca con Google

• Blanchard R.L., Freimuth R.R., Buck J., Weinshilboum R.M., Coughtrie M.W. A proposed nomenclature system for the cytosolic sulfotransferase (SULT) superfamily, Pharmacogenetics. 2004; 14:199-211. Cerca con Google

• Bohnert T., Patel A., Templeton I., Chen Y., Lu C., Lai G., Leung L., Tse S., Einolf H.J., Wang Y., Sinz M., Stearns R., Walsky R., Geng W., Sudsakorn S., Moore D., He L., Wahlstrom J., Keirns J., Narayanan R., Lang D., Yang X. Evaluation of a new molecular entity as a victim of metabolic drug-drug interactions-an industry perspective, Drug Metab Dispos, 2016; 44:1399-1423. Cerca con Google

• Bortolozzi R., Mattiuzzo E., Dal Pra M., Sturlese M., Moro S., Hamel E., Carta D., Viola G., Ferlin M.G. Targeting tubulin polymerization by novel 7-aryl-pyrroloquinolinones: Synthesis, biological activity and SARs, Eur J Med Chem. 2018; 143:244-258. Cerca con Google

• Bradford L.D. The etnopharmacology of atypical antipsychothics, CNS Spectr. 2005; 10:6-12. Cerca con Google

• Caccuri A.M., Ascenzi P., Antonini G., Parker M.W., Oakley A.J., Chiessi E., Nuccetelli M., Battistoni A., Bellizia A., Ricci G. Structural flexibility modulates the activity of human glutathione transferase P1-1. Influence of a poor co-substrate on dynamics and kinetics of human glutathione transferase, J Biol Chem. 1996; 271:16193-8. Cerca con Google

• Calderan L., Caratterizzazione preclinical in vitro di nuovi inibitori non peptidomimetici della glutatione trasferasi P1-1 [Tesi di Dottorato] 2015. Cerca con Google

• Carta D., Bortolozzi R., Sturlese M., Salmaso V., Hamel E., Basso G., Calderan L., Quintieri L., Moro S., Viola G., Ferlin M.G. Synthesis, structure-activity relationships and biological evaluation of 7-phenyl-pyrroloquinolinone 3-amide derivatives as potent antimitotic agents, Eur J Med Chem. 2017; 127:643-660. Cerca con Google

• Cavallito J.C., Nichol C.A., Brenckman W.D. Jr, Deangelis R.L., Stickney D.R., Simmons W.S., Sigel C.W. Lipid-soluble inhibitors of dihydrofolate reductase. I. Kinetics, tissue distribution, and extent of metabolism of pyrimethamine, metoprine, and etoprine in the rat, dog, and man, Drug Metab Dispos. 1978; 6:329-37. Cerca con Google

• Clarke S.E., Harrell A.W., Chenery R.J. Role of aldehyde oxidase in the in vitro conversion of famciclovir to penciclovir in human liver, Drug Metab Dispos. 1995; 23:251-4. Cerca con Google

• Coughtrie M.W.H. Function and organization of the human cytosolic sulfotransferase (SULT) family, Chem Biol Interact. 2016; 259(Pt A):2-7. Cerca con Google

• Dai D., Bai R., Hodgson E., Rose RL. Cloning, sequencing, heterologous expression, and characterization of murine cytochrome P450 3a25*(Cyp3a25), a testosterone 6beta-hydroxylase, J Biochem Mol Toxicol. 2001; 15:90-9. Cerca con Google

• Dalzoppo D., Di Paolo V., Calderan L., Pasut G., Rosato A., Caccuri A.M., Quintieri L. Thiol-Activated Anticancer Agents: The State of the Art, Anticancer Agents Med Chem. 2017;17:4-20. Cerca con Google

• De Luca A., Rotili D., Carpanese D., Lenoci A., Calderan L., Scimeca M., Mai A., Bonanno E., Rosato A., Geroni C., Quintieri L., Caccuri A.M. A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts, Oncotarget. 2015; 6:4126-43. Cerca con Google

• Di L. Reaction phenotyping to assess victim drug-drug interaction risks, Expert Opin Drug Discov. 2017; 12:1105-1115. Cerca con Google

• Duanmu Z., Weckle A., Koukouritaki S.B., Hines R.N., Falany J.L., Falany C.N., Kocarek T.A., Runge-Morris M. Developmental expression of aryl, estrogen, and hydroxysteroid sulfotransferases in pre- and postnatal human liver, J Pharmacol Exp Ther. 2006; 316:1310-7. Cerca con Google

• Dumontet C., Jordan M.A. Microtubule-binding agents: a dynamic field of cancer therapeutics, Nat Rev Drug Discov. 2010; 9:790-803. Cerca con Google

• Dunn R.T., Klaassen C.D. Tissue-specific expression of rat sulfotransferase messenger RNAs, Drug Metab Dispos. 1998; 26:598-604. Cerca con Google

• Durant S., Karran P. Vanillins--a novel family of DNA-PK inhibitors, Nucleic Acids Res. 2003; 31:5501-12. Cerca con Google

• Edenberg H.J., Bosron W.F. Alcohol Dehydrogenases In: Comprehensive Toxicology. McQueen, CA., editor. Oxford:Academic Press; 2010. p. 111-130. Cerca con Google

• Fang B. Genetic Interactions of STAT3 and Anticancer Drug Development, Cancers (Basel). 2014; 6:494-525. Cerca con Google

• Federici L., Lo Sterzo C., Pezzola S., Di Matteo A., Scaloni F., Federici G., Caccuri A.M. Structural basis for the binding of the anticancer compound 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol to human glutathione s-transferases, Cancer Res. 2009; 69:8025-34. Cerca con Google

• Ferlin M.G., Chiarelotto G., Gasparotto V., Dalla Via L., Pezzi V., Barzon L., Palù G., Castagliuolo I. Synthesis and in vitro and in vivo antitumor activity of 2-phenylpyrroloquinolin-4-ones, J Med Chem. 2005; 48:3417-27. Cerca con Google

• Ferone R., Dihydrofolate reductase from pyrimethamine-resistant Plasmodium berghei, J. Biol. Chem.,1970; 245:850-854. Cerca con Google

• Filomeni G., Turella P., Dupuis M.L., Forini O., Ciriolo M.R., Cianfriglia M., Pezzola S., Federici G., Caccuri A.M. 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, a specific glutathione S-transferase inhibitor, overcomes the multidrug resistance (MDR)-associated protein 1-mediated MDR in small cell lung cancer, Mol Cancer Ther. 2008; 7:371-9. Cerca con Google

• Foti R.S. e Dalvie D.K. Cytochrome P450 and Non-Cytochrome P450 oxidative metabolism: contributions to the pharmacokinetics, safety, and efficacy of xenobiotics, Drug Metab Dispos, 2016; 44:1229-1245. Cerca con Google

• Fu C., Di L., Han X., Soderstrom C., Snyder M., Troutman M.D., Obach R.S., Zhang H. Aldehyde oxidase 1 (AOX1) in human liver cytosols: quantitative characterization of AOX1 expression level and activity relationship, Drug Metab Dispos. 2013; 41:1797804. Cerca con Google

• Fulci C., Rotili D., De Luca A., Stella L., Morozzo Della Rocca B., Forgione M., Di Paolo V., Mai A., Falconi M., Quintieri L., Caccuri A.M., A new nitrobenzoxadiazole-based GSTP1-1 inhibitor with a previously unheard of mechanism of action and high stability, J Enzyme Inhib Med Chem. 2017;32:240-247. Cerca con Google

• Gamage N., Barnett A., Hempel N., Duggleby R.G., Windmill K.F., Martin J.L., McManus M.E. Human sulfotransferases and their role in chemical metabolism, Toxicol Sci. 2006;90:5-22. Cerca con Google

• Garattini E., Terao M. Aldehyde oxidase and its importance in novel drug discovery: present and future challenges, Expert Opin Drug Discov. 2013;8:641-54. Cerca con Google

• Giammarioli A.M., Maselli A., Casagrande A., Gambardella L., Gallina A., Spada M., Giovannetti A., Proietti E., Malorni W., Pierdominici M. Pyrimethamine induces apoptosis of melanoma cells via a caspase and cathepsin double-edged mechanism, Cancer Res. 2008; 68:5291-300. Cerca con Google

• Gildenhuys S., Wallace L.A., Burke J.P., Balchin D., Sayed Y., Dirr H.W. Class Pi glutathione transferase unfolds via a dimeric and not monomeric intermediate: functional implications for an unstable monomer, Biochemistry. 2010; 49:5074-81. Cerca con Google

• Godwin P., Baird A.M., Heavey S., Barr M.P., O'Byrne K.J., Gately K. Targeting nuclear factor-kappa B to overcome resistance to chemotherapy, Front Oncol. 2013; 3:120. Cerca con Google

• Gunnarsdottir S., Elfarra A.A. Glutathione-dependent metabolism of cis-3-(9H-purin-6-ylthio)acrylic acid to yield the chemotherapeutic drug 6-mercaptopurine: evidence for two distinct mechanisms in rats, J Pharmacol Exp Ther. 1999; 290:950-7. Cerca con Google

• Habig, W.H., Pabst M.J., Jacobi W.B., Glutathione S-transferases: The first enzymatic step in mercapturic acid formation, J. Biol. Chem., 1974; 249:7130-7139. Cerca con Google

• Harper T.W., Brassil P.J. Reaction phenotyping: current industry efforts to identify enzymes responsible for metabolizing drug candidates, AAPS J. 2008;10:200-7. Cerca con Google

• Hayes J.D., Flanagan J.U., Jowsey I.R. Glutathione transferases, Annu Rev Pharmacol Toxicol. 2005;45:51-88. Cerca con Google

• Hayes J.D., Pulford D.J. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance, Crit Rev Biochem Mol Biol. 1995; 30:445-600. Cerca con Google

• Hebbring S.J., Adjei A.A., Baer J.L., Jenkins G.D., Zhang J., Cunningham J.M., Schaid D.J., Weinshilboum R.M., Thibodeau S.N. Human SULT1A1 gene: copy number differences and functional implications, Hum Mol Genet. 2007; 16:463-70. Cerca con Google

• Hinchman C.A., Ballatori N. Glutathione-degrading capacities of liver and kidney in different species, Biochem Pharmacol., 1990; 40:1131-5. Cerca con Google

• Hinchman C.A., Matsumoto H., Simmons T.W., Ballatori N., Intrahepatic conversion of a glutathione conjugate to its mercapturic acid. Metabolism of 1-chloro-2,4-dinitrobenzene in isolated perfused rat and guinea pig livers, J Biol Chem. 1991; 266:22179-85. Cerca con Google

• Hubbell J.P., Henning M.L., Grace M.E., Nichol C.A., Sigel C.W. N-oxide metabolites of the 2,4-diaminopyrimidine inhibitors of dihydrofolate reductase, trimethoprim, pyrimethamine and metoprine. In: Garrod J.W. (ed) Biological oxidation of nitrogen, Elsevier-North Holland Biomedical, New York, 1978; pp. 177-182. Cerca con Google

• Hutzler J.M., Cook J., Fleishaker J.C. Pharmacokinetics In Drug Development Advances and Application, Volume 3 Bonate P.L., Howard D.R. (Eds.) 2011, XII, 21-56p. Cerca con Google

• Islam M.N., Iskander M.N. Microtubulin binding sites as target for developing anticancer agents, Mini Rev Med Chem. 2004; 4:1077-104. Cerca con Google

• Jackson B., Brocker C., Thompson D.C., Black W., Vasiliou K., Nebert D.W., Vasiliou V. Update on the aldehyde dehydrogenase gene (ALDH) superfamily, Hum Genomics. 2011; 5:283-303. Cerca con Google

• James M.O., Ambadapadi S. Interactions of cytosolic sulfotransferases with xenobiotics, Drug Metab Rev. 2013; 45:401-14. Cerca con Google

• Kavallaris M. Microtubules and resistance to tubulin-binding agents, Nat Rev Cancer. 2010; 10:194-204. Cerca con Google

• Kawai M., Bandiera S.M., Chang T.K., Bellward G.D. Growth hormone regulation and developmental expression of rat hepatic CYP3A18, CYP3A9 and CYP3A2, Biochem Pharmacol, 2000; 59:1277-87. Cerca con Google

• Keppler D. Export pumps for glutathione S-conjugates, Free Radic Biol Med. 1999; 27:985-91. Cerca con Google

• Khan M.W., Saadalla A., Ewida A.H., Al-Katranji K., Al-Saoudi G., Giaccone Z.T., Gounari F., Zhang M., Frank D.A., Khazaie K. The STAT3 inhibitor pyrimethamine displays anti-cancer and immune stimulatory effects in murine models of breast cancer, Cancer Immunol Immunother. 2018; 67:13-23. Cerca con Google

• Kirchmair J., Göller A.H., Lang D., Kunze J., Testa B., Wilson I.D., Glen R.C., Schneider G. Predicting drug metabolism: experiment and/or computation? Nat Rev Drug Discov. 2015; 14:387-404. Cerca con Google

• Kishida T., Muto S., Hayashi M., Tsutsui M., Tanaka S., Murakami M., Kuroda J. Strain differences in hepatic cytochrome P450 1A and 3A expression between Sprague-Dawley and Wistar rats. J Toxicol Sci. 2008; 33:447-57. Cerca con Google

• Koppaka V., Thompson D.C., Chen Y., Ellermann M., Nicolaou K.C., Juvonen R.O., Petersen D., Deitrich R.A., Hurley T.D., Vasiliou V. Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application, Pharmacol Rev. 2012; 64:520-39. Cerca con Google

• Kueh H.Y., Mitchison T.J. Structural plasticity in actin and tubulin polymer dynamics, Science. 2009; 325:960-3. Cerca con Google

• Laborde E. Glutathione transferases as mediators of signaling pathways involved in cell proliferation and cell death, Cell Death Differ. 2010; 17:1373-80. Cerca con Google

• Lin J.H. e Lu A.Y. Role of pharmacokinetics and metabolism in drug discovery and development, Pharmacol Rev. 1997; 49:403-49. Cerca con Google

• Lirdprapamongkol K., Kramb J.P., Suthiphongchai T., Surarit R., Srisomsap C., Dannhardt G., Svasti J. Vanillin suppresses metastatic potential of human cancer cells through PI3K inhibition and decreases angiogenesis in vivo, J Agric Food Chem. 2009; 57:3055-63. Cerca con Google

• Lirdprapamongkol K., Sakurai H., Kawasaki N., Choo M.K., Saitoh Y., Aozuka Y., Singhirunnusorn P., Ruchirawat S., Svasti J., Saiki I. Vanillin suppresses in vitro invasion and in vivo metastasis of mouse breast cancer cells, Eur J Pharm Sci. 2005; 25:57-65. Cerca con Google

• Ma B., Schrag M. Sulfotransferases In: Encyclopedia of Drug Metabolism and Interactions. 2012; Edited by Alexander V. Lyubimov, First Edition 6-Volume Set. Cerca con Google

• Mahnke A., Strotkamp D., Roos P.H., Hanstein W.G., Chabot G.G., Nef P. Expression and inducibility of cytochrome P450 3A9 (CYP3A9) and other members of the CYP3A subfamily in rat liver, Arch Biochem Biophys. 1997; 337:62-8. Cerca con Google

• Marchitti S.A., Brocker C., Stagos D., Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily, Expert Opin Drug Metab Toxicol. 2008; 4:697-720. Cerca con Google

• Marto N., Morello J., Monteiro E.C., Pereira S.A. Implications of sulfotransferase activity in interindividual variability in drug response: clinical perspective on current knowledge, Drug Metab Rev. 2017; 49:357-371. Cerca con Google

• Marton A., Kúsz E., Kolozsi C., Tubak V., Zagotto G., Buzás K., Quintieri L., Vizler C. Vanillin Analogues o-Vanillin and 2,4,6-Trihydroxybenzaldehyde Inhibit NFĸB Activation and Suppress Growth of A375 Human Melanoma, Anticancer Res. 2016;36:5743-5750. Cerca con Google

• Meerman J.H., Ringer D.P., Coughtrie M.W., Bamforth K.J., Gilissen R.A. Sulfation of carcinogenic aromatic hydroxylamines and hydroxamic acids by rat and human sulfotransferases: substrate specificity, developmental aspects and sex differences, Chem Biol Interact. 1994; 92:321-8. Cerca con Google

• Mugford C.A. e Kedderis G.L. Sex-dependent metabolism of xenobiotics, Drug Metab Rev, 1998; 30:441-98. Cerca con Google

• Mukhtar E., Adhami V.M., Mukhtar H. Targeting microtubules by natural agents for cancer therapy, Mol Cancer Ther. 2014;13:275-84. Cerca con Google

• Murphy C.D., Sandford G. Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity. Expert Opin Drug Metab Toxicol. 2015;11:589-99. Cerca con Google

• Nagar S., Walther S., Blanchard R.L. Sulfotransferase (SULT) 1A1 polymorphic variants *1, *2, and *3 are associated with altered enzymatic activity, cellular phenotype, and protein degradation, Mol Pharmacol. 2006; 69:2084-92. Cerca con Google

• Nelson D.R., Zeldin D.C., Hoffman S.M., Maltais L.J., Wain H.M., Nebert D.W. Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes, including nomenclature recommendations for genes, pseudogenes and alternative-splice variants, Pharmacogenetics. 2004;14:1-18. Cerca con Google

• Nelson E.A., Sharma S.V., Settleman J., Frank D.A. A chemical biology approach to developing STAT inhibitors: molecular strategies for accelerating clinical translation, Oncotarget. 2011; 2:518-24. Cerca con Google

• Nicholas J.S. e Barron D.H. The use of sodium amytal in the production of anesthesia in the rat, J Pharmacol Exp Ther. 1932; 46:125-129. Cerca con Google

• Obach R.S. Inhibition of human Cytochrome P450 enzymes by constituents of St. John’s Wort, an Herbal Preparation used in the treatment of depression. JPET. 2000; 294:88-95. Cerca con Google

• Ono S., Hatanaka T., Hotta H., Satoh T., Gonzalez F.J., Tsutsui M. Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes, Xenobiotica. 1996; 26:681-93. Cerca con Google

• Panoutsopoulos G.I., Beedham C., Enzymatic oxidation of vanillin, isovanillin and protocatechuic aldehyde with freshly prepared Guinea pig liver slices, Cell Physiol Biochem, 2005;15:89-98. Cerca con Google

• Panoutsopoulos G.I., Kouretas D., Beedham C., Contribution of aldehyde oxidase, xanthine oxidase, and aldehyde dehydrogenase on the oxidation of aromatic aldehydes, Chem Res Toxicol, 2004; 17:1368-1376. Cerca con Google

• Park E.J., Lee Y.M., Oh T.I., Kim B.M., Lim B.O., Lim J.H. Vanillin Suppresses Cell Motility by Inhibiting STAT3-Mediated HIF-1α mRNA Expression in Malignant Melanoma Cells, Int J Mol Sci. 2017; 18(3). Cerca con Google

• Parkinson e Ogilvie Biotrasformazione degli xenobiotici in Casarett&Doull’s – Tossicologia - I fondamenti dell’azione delle sostanze tossiche, EMSI, settima edizione italiana, 2010. Cerca con Google

• Pasello M., Manara M.C., Michelacci F., Fanelli M., Hattinger C.M., Nicoletti G., Landuzzi L., Lollini P.L., Caccuri A., Picci P., Scotlandi K., Serra M. Targeting glutathione-S transferase enzymes in musculoskeletal sarcomas: a promising therapeutic strategy, Anal Cell Pathol (Amst). 2011; 34:131-45. Cerca con Google

• Pryde D.C., Dalvie D., Hu Q., Jones P., Obach R.S., Tran T.D. Aldehyde oxidase: an enzyme of emerging importance in drug discovery, J Med Chem. 2010; 53:8441-60. Cerca con Google

• Quintanilla M.E., Tampier L., Sapag A., Gerdtzen Z., Israel1 Y. Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective, Am J Physiol Endocrinol Metab. 2007; 293:E531-7. Cerca con Google

• Quintieri L Biotrasformazione dei farmaci. In: Dorigo P. Farmacologia generale III ed. CEDAM, pp 144-173. Padova, 2006. Cerca con Google

• Quintieri L., Fantin M., Palatini P., De Martin S., Rosato A., Caruso M., Geroni C., Floreani M. In vitro hepatic conversion of the anticancer agent nemorubicin to its active metabolite PNU-159682 in mice, rats and dogs: a comparison with human liver microsomes, Biochem Pharmacol. 2008;76:784-95. Cerca con Google

• Rastogi H., Jana S. Evaluation of inhibitory effects of caffeic acid and quercetin on human liver cytochrome p450 activities. Phytother Res. 2014; 28:1873-8. Cerca con Google

• Renaud H.J., Cui J.Y., Khan M., Klaassen C.D. Tissue distribution and gender-divergent expression of 78 cytochrome P450 mRNAs in mice, Toxicol Sci. 2011; 124:261-77. Cerca con Google

• Ricci G., De Maria F., Antonini G., Turella P., Bullo A., Stella L., Filomeni G., Federici G., Caccuri A.M. 7-Nitro-2,1,3-benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs, J Biol Chem. 2005; 280:26397-405. Cerca con Google

• Riches Z., Stanley E.L., Bloomer J.C., Coughtrie M.W. Quantitative evaluation of the expression and activity of five major sulfotransferases (SULTs) in human tissues: the SULT "pie", Drug Metab Dispos. 2009; 37:2255-61. Cerca con Google

• Rinn J.L., Rozowsky J.S., Laurenzi I.J., Peterson P.H., Zou K., Zhong W., Gerstein M., Snyder M. Major molecular differences between mammalian sexes are involved in drug metabolism and renal function, Dev Cell, 2004; 6:791-800. Cerca con Google

• Romão M.J., Coelho C., Santos-Silva T., Foti A., Terao M., Garattini E., Leimkühler S. Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics, Curr Opin Chem Biol. 2017; 37:39-47. Cerca con Google

• Ross M. K., Borazjani A., Wang R., Crow J. A., Xie S., Examination of the carboxylesterase phenotype in human liver, Archives of Biochemistry and Biophysics, 2012; 522:42-56. Cerca con Google

• Ruzza P., Rosato A., Rossi C.R., Floreani M., Quintieri L. Glutathione transferases as targets for cancer therapy, Anticancer Agents Med Chem. 2009; 9:763-77. Cerca con Google

• Sakuma T., Endo Y., Mashino M., Kuroiwa M., Ohara A., Jarukamjorn K., Nemoto N. Regulation of the expression of two female-predominant CYP3A mRNAs (CYP3A41 and CYP3A44) in mouse liver by sex and growth hormones, Arch Biochem Biophys. 2002; 404:234-42. Cerca con Google

• Sakuma T., Takai M., Endo Y., Kuroiwa M., Ohara A., Jarukamjorn K., Honma R., Nemoto N. A novel female-specific member of the CYP3A gene subfamily in the mouse liver, Arch Biochem Biophys. 2000; 377:153-62. Cerca con Google

• Sanoh S., Tayama Y., Sugihara K., Kitamura S., Ohta S. Significance of aldehyde oxidase during drug development: Effects on drug metabolism, pharmacokinetics, toxicity, and efficacy, Drug Metab Pharmacokinet. 2015; 30:52-63. Cerca con Google

• Sau A., Pellizzari Tregno F., Valentino F., Federici G., Caccuri A.M. Glutathione transferases and development of new principles to overcome drug resistance, Arch Biochem Biophys. 2010; 500:116-22. Cerca con Google

• Shapiro B.H., Agraval A.K., Pampori N.A. Gender differences in drug metabolism regulated by growth hormone, Int J Biochem Cell Biol, 1995; 27:9-20. Cerca con Google

• Simic T., Savic-Radojevic A., Pljesa-Ercegovac M., Matic M., Mimic-Oka J. Glutathione S-transferases in kidney and urinary bladder tumors, Nat Rev Urol. 2009; 6:281-9. Cerca con Google

• Simon F.R., Fortune J., Iwahashi M., Sutherland E. Sexual dimorphic expression of ADH in rat liver: importance of the hypothalamic-pituitary-liver axis, Am J Physiol Gastrointest Liver Physiol. 2002; 283:G646-55. Cerca con Google

• Steinmetz M.O., Prota A.E. Microtubule-Targeting Agents: Strategies To Hijack the Cytoskeleton, Trends Cell Biol. 2018 Epub ahead of print PMID 29871823. Cerca con Google

• Suiko M., Kurogi K., Hashiguchi T., Sakakibara Y., Liu M.C. Updated perspectives on the cytosolic sulfotransferases (SULTs) and SULT-mediated sulfation, Biosci Biotechnol Biochem. 2017; 81:63-72. Cerca con Google

• Tayama Y., Moriyasu A., Sugihara K., Ohta S., Kitamura S. Developmental changes of aldehyde oxidase in postnatal rat liver, Drug Metab Pharmacokinet. 2007; 22:119-24. Cerca con Google

• Tayama Y., Sugihara K., Sanoh S., Miyake K., Kitamura S., Ohta S. Developmental changes of aldehyde oxidase activity and protein expression in human liver cytosol, Drug Metab Pharmacokinet. 2012; 27:543-7. Cerca con Google

• Terao M., Romão M.J., Leimkühler S., Bolis M., Fratelli M., Coelho C., Santos-Silva T., Garattini E. Structure and function of mammalian aldehyde oxidases, Arch Toxicol. 2016; 90:753-80. Cerca con Google

• Tilborghs S., Corthouts J., Verhoeven Y., Arias D., Rolfo C., Trinh X.B., van Dam P.A. The role of Nuclear Factor-kappa B signaling in human cervical cancer, Crit Rev Oncol Hematol. 2017; 120:141-150. Cerca con Google

• Tingle M.D. e Helsby N.A. Can in vitro drug metabolism studies with human tissue replace in vivo animal studies?, Environmental Toxicology and Pharmacology, 2006; 21:184-190. Cerca con Google

• Tommasino C., Gambardella L., Buoncervello M., Griffin R.J., Golding B.T., Alberton M., Macchia D., Spada M., Cerbelli B., d'Amati G., Malorni W., Gabriele L., Giammarioli A.M. New derivatives of the antimalarial drug Pyrimethamine in the control of melanoma tumor growth: an in vitro and in vivo study, J Exp Clin Cancer Res. 2016; 35:137. Cerca con Google

• Townsend D.M., Tew K.D. The role of glutathione-S-transferase in anti-cancer drug resistance, Oncogene. 2003; 22:7369-75. Cerca con Google

• Turella P., Filomeni G., Dupuis M.L., Ciriolo M.R., Molinari A., De Maria F., Tombesi M., Cianfriglia M., Federici G., Ricci G., Caccuri A.M. A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells. 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells, J Biol Chem. 2006; 281:23725-32. Cerca con Google

• Venkatachalam K.V. Human 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase: biochemistry, molecular biology and genetic deficiency, IUBMB Life. 2003; 55:1-11. Cerca con Google

• Wang X., Crowe P.J., Goldstein D., Yang J.L. STAT3 inhibition, a novel approach to enhancing targeted therapy in human cancers (review), Int J Oncol. 2012; 41:1181-91. Cerca con Google

• Waxman D.J. e Holloway M.G. Sex differences in the expression of hepatic drug metabolizing enzymes, Mol Pharmacol. 2009; 76:215-228. Cerca con Google

• Williams J.A., Hurst S.I., Bauman J., Jones B.C., Hyland R., Gibbs J.P., Obach R.S., Ball S.E. Reaction phenotyping in drug discovery: moving forward with confidence?, Curr Drug Metab. 2003;4:527-34. Cerca con Google

• Wong K.P., Sourkes T.L. Metabolism of vanillin and related substances in the rat, Can J Biochem. 1966; 44:635-44. Cerca con Google

• Wrighton S.A., Ring B.J., VandenBranden M. The use of in vitro metabolism techniques in the planning and interpretation of drug safety studies, Toxicol Pathol, 1995; 23:199-208. Cerca con Google

• Xia L., Tan S., Zhou Y., Lin J., Wang H., Oyang L., Tian Y., Liu L., Su M., Wang H., Cao D, Liao Q. Role of the NFκB-signaling pathway in cancer, Onco Targets Ther. 2018; 11:2063-2073. Cerca con Google

• Yoshinara S., Tatsumi K. Purification and characterization of hepatic aldehyde oxidase in male and female mice, Arch Biochem Biophys. 1997; 338:29-34. Cerca con Google

• Yu J., Han J.C., Hua L.M., Gao Y.J. In vitro characterization of glucuronidation of vanillin: identification of human UDP-glucuronosyltransferases and species differences, Phytother Res. 2013; 27:1392-7. Cerca con Google

• Zhang H., Davis C.D., Sinz M.W., Rodrigues A.D. Cytochrome P450 reaction-phenotyping: an industrial perspective, Expert Opin Drug Metab Toxicol. 2007; 3:667-87. Cerca con Google

• Zientek M.A., Youdim K. Reaction phenotyping: advances in the experimental strategies used to characterize the contribution of drug-metabolizing enzymes, Drug Metab Dispos. 2015; 43:163-81. Cerca con Google

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