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Pegolo, Sara (2010) Enzimi farmaco-metabolizzanti epatici in specie di interesse veterinario. [Ph.D. thesis]

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Abstract (english)

In veterinary medicine, the characterisation of the P450 isoenzymes is still incomplete and moreover, the substrates used were selected on the basis of the available knowledge from experiments in human or laboratory species without any kinetic or inhibition study (Fink-Gremmels, 2008). Defining the contribution of a P450 isoform in the metabolism of a specific drug is of great interest not only for veterinary pharmacology and toxicology but also for human health, for the potential presence of toxic residues in food animal products.
During the PhD course, projects dealing with the evaluation of cytochrome P450 activities in veterinary species have been developed. The aim was to increase knowledge about drug metabolizing enzymes in veterinary species and about the modulation of their activity. The modulation may be due to factors as breed but also exposure to environmental contaminants or somministration of illicit drugs used to enhance growth and consequently increase profit (Johnson, 2007). Data collected from these in vitro studies can be actually used to evaluate the effects of drug-drug interactions and for the plan of experimental projects aiming to identify in vivo markers of exposure or treatment.
I) Determination of CYP1A and CYP2C activities in bovine liver. In this study, accuracy, precision, LOD and LOQ of High Performance Liquid Chromatography (HPLC) methods previously developed in the lab for the evaluation of ethoxyresorufin-O-deethylase (EROD) e tolbutamide methyl-hydroxylase (TMOH) activities, have been determined. The aim was to calculate the enzyme kinetic parameters: respectively 0.23 ± 0.051 and 1010 ± 155.7 μM for Km and 0.488 ± 0.035 and 0.089 ± 0.006 nmol/min/mg protein for Vmax. The methods were proved to be so sensitive to determine also very low levels of enzyme activity as those of veal calves fed with milk replacers and low iron content diet. Finally, to verify the presence of intra-specific differences in enzyme activity, EROD and TMOH were determined with liver microsomes from Charolais (CH), Blonde D’Aquitaine (BD) and Piedmontese (PM). The results of EROD evidenced higher activity in CH vs PM (p<0.05). So, for the first time, the presence of breed differences in this enzyme activity was established, confirming also what reported by other authors for CYP3A-dependent activities (Dacasto et al., 2005). These differences may influence bioavailability and clinical efficacy of xenobiotics (Sallovitz et al., 2002) and may be of particular interest in veterinary species for the potential presence of toxic residues in food animal products.
II) Testosterone hydroxylation in bovine liver: enzyme kinetic and inhibition study. This study evaluated, by HPLC analysis, the kinetic of testosterone (TST) hydroxylase activities in vitro, with liver microsomes from cattle. Kinetic parameters for 6b–, 16b– and 2b –TST hydroxylase activities (OHT) were 93.4±13.8, 36.4±6.1 and 110.8±15.2 ±M respectively for Km and 0.558±0.03, 0.280±0.013 and 0.338±0.017 nmol/min/mg protein for Vmax.. Moreover, chemical inhibition studies with a CYP3A inhibitor (ketoconazole) and CYP2B inhibitors (orphenadrine and 9-ethynylphenanthrene) were performed to establish the involvement of CYP3A and potentially of CYP2B in these enzyme reactions. To further confirm the results obtained, an anti-peptide antibody against bovine CYP3A4 was also used. The antibody specificity with bovine liver microsomes was evaluated and then immunoinhibition studies were conducted, evidencing > 90% inhibition for 16b– and 2b –OHT activities and > 80% for 6b–OHT. These results seemed to suggest the predominant involvement of CYP3A in the production of the three main TST-hydroxylated metabolites in bovine liver while CYP2B seemed to be not involved.
III) Effects of illicit treatments on CYP3A in bovine liver and in primary cultures of bovine hepatocytes. These experiments intended to prove the applicability of the HPLC method and TST substrate for evaluating CYP3A activity, aiming to actually verify illicit treatments effect and collect more data respect to previous studies in veal calf and beef cattle.
In the first experiment, 6b-, 16b- and 2b-OHT were determined in bovine treated with dexamethasone (D) and dexamethasone+estradiol (DE). The results obtained evidenced a significant induction for 6b- and 16b-OHT in D and DE vs control (K, p<0.05) and for 2b–OHT in D and DE vs K (p<0.05 and p<0.01, respectively), confirming what reported for human (McCune et al., 2000). These results were confirmed by Immunoblotting which evidenced increasing in CYP3A protein expression in D and D+E vs K (p<0.01 and p<0.05, respectively).
In the second experiment, 6b-, 16b- and 2b-OHT were determined in bovine hepatocytes after 24 h incubation with boldenone (B), androsta-1,4-diene-3,17-dione (A) and B + A. The results showed an inhibitory trend in hepatocytes incubated with growth promoters vs controls (K). In particular, 6b and 16b OHT were inhibited in A and B vs K while 2b-OHT in A vs K (p<0.05). At the protein level instead, no significant difference was found in CYP3A expression (Immunoblotting). The inhibitory effect observed may be due to the high doses used; inhibitory/toxic effects of high doses of inducing agents were evidenced for instance by Kostrubsky et al. (1999) who used human hepatocytes to study induction of cytochrome P450, stressing the importance of large dose-response studies as well as the need to assess toxicity in these investigations.
The results obtained in these experiments confirmed the modulation of expression and regulation of cytochrome P450 enzymes by estrogens, corticosteroids and anabolic steroids. There is the need however, to explain deeply for bovine the mechanism through that these compounds act at pre- and post-transcriptional level.
IV) Determination of CYP1A activity in the liver of Zosterisessor ophiocephalus as biomarker of pollution in the Venice Lagoon. Recently, it was proved that biomarkers (BM) are very useful to evidence early biological changes in environmental pollution. One of the most common BM used in fishes is the induction of the P450 system and in particolar ethoxyresorufin O-deethylase activity (EROD) is a marker of fish exposure to potentially toxic compounds, i.e. poli-chlorinated biphenils and polycyclic aromatic hydrocarbons (Burgeot et al., 1994). The aim of this study was to evaluate by HPLC EROD activity in Zosterisessor ophiocephalus, a benthic fish that may represent an useful bioindicator of environmental stress in the Venice Lagoon. Fishes were collected in spring and autumn in three different areas of the Venice Lagoon: Porto Marghera (PM), Valle di Brenta (VB) and Porto Canale (PC); the samples were then classified in females, males and sneakers (small males, < 1 years-old).
Factorial analysis of EROD activity results evidenced that site, fish category and season were significant (p<0,001), and the interactions category*site and category *season as well (p<0,001). Considering site effect in particular, in PM EROD activity values were significantly higher than in VB and in PC (p<0,01 and p<0,001, respectively) and in VB higher than in PC (p<0,01). These results were in agreement with the available data relative to persistent organic pollutants (POPs) concentration (expressed as enrichment factor, EF) in the sediments of the Venice Lagoon, that showed major contamination in the area close to Porto Marghera (EF>12), intermediate in the area of Valle di Brenta (EF=5-12) and low around Porto Canale (EF=1-5; Guerzoni et al., 2004). However, site effect depended on the fish category and in particular differences were found between males and females, due more probably to the analyzed samples than to real differences in induction. From these results, EROD activity may be considered an useful biomarker even if, considering the multifactorial response of individuals, it is important to use several significant biomarkers to accurately evaluate the effects of environmental pollution in the aquatic ecosystem.
V) Luminescence high-throughput methods for determining CYP3A and CYP2C activities in horse liver. In the last part of the thesis, results of kinetic and inhibition studies to evaluate CYP2C and CYP3A activities in horse liver through Glo assays were reported. The aim was to evaluate the performances of this technique for drug metabolism or drug-drug interaction studies. Enzyme kinetic parameters for CYP3A and CYP2C activities were respectively 14.5 ± 7.3 and 175.9 ± 16.2 μM for Km and 0.022 ± 0.0004 and 0.025 ± 0.0009 nmol/min/mg protein for Vmax. Ketoconazole (CYP3A inhibitor) evidenced IC50 values of 0.035 μM, confirming good specificity of the luciferin (L)-derivative substrate used for CYP3A (L-IPA). Sulfaphenazole (CYP2C inhibitor) evidenced IC50 values of 47.2 μM, suggesting the need to conduct further studies to verify substrate specificity (L-H), for instance using other selective inhibitors for the CYP2C subfamily as ibuprofen or diclofenac. Luminescence methods allowed to analyse many samples in short time, to monitor more than one isoform simultaneously in the same plate and showed good sensitivity confirmed by LOD values: 0.2 and 0.11 nM for L-H and L-IPA, respectively. So, these results may represent a good starting point to apply this technique in drug metabolism and drug-drug interaction studies in veterinary species

Abstract (italian)

Nel corso dei tre anni di dottorato sono stati sviluppati progetti relativi alla valutazione dell’attività epatica di isoforme di citocromo P450 in specie di interesse veterinario. In medicina veterinaria, la caratterizzazione del sistema P450 è ancora incompleta; inoltre, i substrati utilizzati sono stati selezionati sulla base delle conoscenze disponibili a partire da esperimenti condotti nell’uomo o nelle specie di laboratorio senza studi di cinetica enzimatica o di inibizione (Fink-Gremmels, 2008). Definire il contributo di un’isoforma di citocromo P450 nel metabolismo di un farmaco specifico è importante non solo per la farmacologia e la tossicologia veterinarie ma anche per la salute dell’uomo, per la possibile presenza di residui nei prodotti di origine animale.
L’obiettivo della presente tesi di dottorato è stato dunque quello di aumentare le conoscenze sugli enzimi che metabolizzano i farmaci in specie di interesse veterinario e sulla modulazione della loro attività. Tale modulazione può essere dovuta a fattori come la razza ma anche all’esposizione ad inquinanti ambientali oppure alla somministrazione di sostanze illecite utilizzate allo scopo di determinare incremento ponderale, riduzione degli indici di conversione alimentare e quindi aumento complessivo del reddito (Johnson, 2007). Le informazioni ottenute con tali studi in vitro dunque possono essere utili per valutare l’effetto di interazioni tra farmaci e per il disegno sperimentale di progetti volti all’identificazione di marker in vivo di esposizione o trattamento.
I) Valutazione dell’attività di CYP1A e CYP2C nel fegato di bovino. Nel presente lavoro, sono stati verificati accuratezza, precisione, LOD e LOQ di metodi in High Performance Liquid Chromatography (HPLC) precedentemente messi a punto nel laboratorio per la valutazione dell’attività di etossiresorufina-O-deetilasi (EROD) e tolbutamide metil-idrossilasi (TMOH) in microsomi epatici di bovino allo scopo di determinare i parametri di cinetica enzimatica: rispettivamente 0,23 ± 0,051 e 1010 ± 155,7 μM per la Km e 0,488 ± 0,035 e 0,089 ± 0,006 nmol/min/mg proteina per laVmax. La sensibilità dei metodi messi a punto ha permesso di valutare anche livelli di attività enzimatica molto bassi come quelli dei vitelli a carne bianca che vengono alimentati con una dieta a base di sostitutivi del latte e basso contenuto di ferro. Infine, per verificare l’esistenza di differenze intra-specifiche nell’attività enzimatica, le attività di EROD e TMOH sono state determinate utilizzando microsomi epatici di bovini di razza Charolais (CH), Blonde D’Aquitaine (BD) e Piemontese (PM). I risultati ottenuti per l’attività di EROD hanno evidenziato una maggiore attività nei bovini di razza CH vs PM (p<0,05). E’ stata dunque dimostrata, per la prima volta, l’esistenza di differenze intra-specifiche dovute alla razza relative a questa attività enzimatica, confermando quanto evidenziato da altri autori in relazione ad attività CYP3A-dipendenti (Dacasto et al., 2003). Tali differenze potrebbero influenzare la biodisponibilità e l’efficacia clinica di xenobiotici (Sallovitz et al., 2002) e potrebbero essere di particolare interesse nelle specie di interesse veterinario per l’ipotetica presenza di residui potenzialmente tossici negli alimenti di origine animale. Per quanto riguarda invece l’attività di TMOH non sono state evidenziate differenze statisticamente significative.
II) Valutazione dell’attività di idrossilazione del testosterone nel fegato di bovino: studio di cinetica enzimatica e di inibizione. In questo studio è stata valutata, tramite analisi in HPLC, la cinetica delle reazioni di idrossilazione del testosterone (TST) in vitro, con microsomi epatici di bovino. I parametri di cinetica enzimatica per le attività di 6b–, 16b– e 2b –TST idrossilasi (OHT) sono risultati 93,4±13,8, 36,4±6,1 e 110,8±15,2 ±M rispettivamente, per la Km e 0,558±0,03, 0,280±0,013 e 0,338±0,017 nmol/min/mg proteina per la Vmax.. Inoltre sono stati effettuati degli studi di inibizione chimica con inibitori di CYP3A (chetoconazolo) e di CYP2B (orfenadrina e 9-etinilfenantrene) per definire il coinvolgimento di CYP3A e potenzialmente di CYP2B in queste reazioni enzimatiche. I risultati ottenuti sono stati ulteriormente confermati con l’impiego di un anticorpo anti-peptide contro CYP3A4 di bovino. Dopo aver valutato la sua specificità con microsomi epatici di bovino, sono stati effettuati degli studi di immunoinibizione, che hanno evidenziato un’inibizione > 90% per le attività di 16b– e 2b –OHT e > 80% per 6b–OHT. Nel complesso, questi risultati sembrerebbero suggerire il coinvolgimento predominante di CYP3A nella produzione dei tre principali metaboliti del TST nel fegato di bovino mentre CYP2B non sembrerebbe essere coinvolto.
III) Effetti di trattamenti illeciti su CYP3A nel fegato del bovino da carne e in colture primarie di epatociti di bovino. L’obiettivo principale di entrambe le prove sperimentali descritte è stato quello di dimostrare l’applicabilità del metodo HPLC e del substrato TST per la valutazione dell’attività enzimatica CYP3A-dipendente, allo scopo di verificare l’effetto del trattamento e di acquisire ulteriori evidenze sperimentali rispetto ai risultati di studi precedentemente coinvolti dal nostro gruppo di ricerca sul vitello a carne bianca e sul vitellone.
In un primo esperimento, sono state determinate le attività di 6b-, 16b- e 2b-OHT in microsomi epatici di bovini trattati con desametazone (D) e desametazone + estradiolo (DE). I risultati ottenuti hanno evidenziato un’induzione statisticamente significativa nelle attività di 6b- e 16b-OHT in D e DE vs controlli (K, p<0,05) e nell’attività di 2b–OHT in D e DE vs K (p<0,05 e p<0,01, rispettivamente), confermando quanto riportato in letteratura per l’uomo (McCune et al., 2000). Tali risultati sono stati convalidati ulteriormente dall’analisi in Immunoblotting che ha evidenziato un aumento dell’espressione di CYP3A in D e D+E vs K (p<0,01 e p<0,05, rispettivamente).
In un secondo esperimento, sono state determinate le attività di 6b-, 16b- e 2b-OHT in epatociti di bovino dopo 24 h di incubazione con boldenone (B), androsta-1,4-diene-3,17-dione (A) e B + A. I risultati ottenuti hanno evidenziato un trend inibitorio negli epatociti incubati con promotori di crescita rispetto a K. In particolare, le attività di 6b e 16b OHT sono state inibite in A e B vs K mentre l’attività di 2b-OHT in A vs K (p<0,05). A livello di proteina invece, non è stata riscontrata alcuna differenza statisticamente significativa nell’espressione di CYP3A (Immunoblotting). L’effetto inibitorio osservato potrebbe essere dovuto alle dosi utilizzate; un caso di effetto inibitorio/tossico di alte dosi di sostanze inducenti è riportato da Kostrubsky et al. (1999) che hanno utilizzato epatociti di uomo per studiare l’induzione del sistema citocromo P450 evidenziando la necessità di effettuare degli studi dose-risposta in un ampio range di concentrazioni delle sostanze utilizzate e di valutarne la tossicità.
Nel complesso, i risultati ottenuti in questi due esperimenti hanno confermato la modulazione da parte di estrogeni, corticosteroidi ed anabolizzanti dell’espressione e la regolazione degli enzimi citocromo P450-dipendenti. Chiaramente, rimane comunque la necessità di spiegare più approfonditamente per quanto riguarda il bovino i meccanismi tramite i quali queste sostanze agiscono sia a livello pre-trascrizionale che post-trascrizionale.
IV) Valutazione dell’attività di CYP1A nel fegato di Zosterisessor ophiocephalus come biomarcatore di inquinamento nella laguna di Venezia. Recentemente, è stato dimostrato che i biomarcatori (BM) sono molto utili per rilevare dei cambiamenti biologici precoci nell’inquinamento ambientale. Uno dei BM più comunemente usati nei pesci è l’induzione dell’attività di etossiresorufina-O-deetilasi (EROD) che è un indicatore dell’esposizione dell’organismo a composti potenzialmente tossici, come ad esempio i policloro-bifenili e gli idrocarburi aromatici policiclici (Burgeot et al., 1994). Di conseguenza, lo scopo del presente lavoro è stato quello di valutare l’attività di EROD tramite HPLC in Zosterisessor ophiocephalus, una specie bentonica che date le sue caratteristiche, può rappresentare un utile indicatore biologico dei livelli di stress ambientale presente nella Laguna di Venezia. I pesci sono stati raccolti in primavera ed in autunno in tre aree della Laguna di Venezia: Porto Marghera (PM), Valle di Brenta (VB) e Porto Canale (PC); i campioni sono stati poi suddivisi in femmine, maschi e sneakers (maschi giovani). L’analisi fattoriale ha evidenziato la significatività dei fattori sito, categoria e stagione (p<0,001) ma anche delle interazioni categoria*sito e categoria*stagione (p<0,01). Per quanto riguarda l’effetto del sito in particolare, PM possedeva valori di attività di EROD significativamente più elevati rispetto a VB e PC (p<0,01 e p<0,001, rispettivamente) e VB rispetto a PC (p<0,001). Tali risultati sembrerebbero essere in accordo con i dati disponibili relativi alla concentrazione di inquinanti organici persistenti (POP) espressa come fattore di arricchimento (EF) nei sedimenti della Laguna di Venezia, i quali indicano una contaminazione maggiore nell’area circostante a Marghera (EF>12), intermedia nei pressi di Valle di Brenta (EF=5-12) e ridotta nel territorio contiguo al sito di Porto Canale (EF=1-5; Guerzoni et al., 2004). L’effetto del sito dipendeva comunque dalla categoria di animali considerata ed in particolare sono state evidenziate delle differenze tra maschi e femmine, dovute probabilmente comunque al campione analizzato più che a differenze reali in termini di induzione. Dai risultati ottenuti, l’attività di EROD è da considerarsi un buon biomarcatore anche se, considerando la natura multifattoriale della risposta dell’individuo, è necessario l’utilizzo congiunto di più biomarcatori significativi per effettuare una valutazione accurata degli effetti dell’inquinamento nell’ecosistema acquatico.
V) Messa a punto di metodi high-throughput in luminescenza per la valutazione dell’attività di CYP3A e di CYP2C nel fegato di cavallo. Nell’ultimo capitolo della tesi, sono riportati i risultati relativi agli studi di cinetica enzimatica e di inibizione chimica volti alla valutazione delle attività di CYP2C e CYP3A nel fegato di cavallo mediante l’utilizzo di saggi Glo. Lo scopo è stato quello di valutare le performance di questa tecnologia allo scopo di applicarla in studi di metabolismo e di interazioni tra farmaci. I parametri di cinetica enzimatica per le attività di CYP3A e di CYP2C sono risultati rispettivamente 14,5 ± 7,3 e 175,9 ± 16,24 μM per la Km e 0,022 ± 0,004 e 0,025 ± 0,0009 nmol/min/mg proteina per la Vmax. Chetoconazolo (inibitore di CYP3A) ha evidenziato un valore di IC50 pari a 0,035 μM, confermando quindi una buona specificità del substrato luciferina (L)-derivato utilizzato per CYP3A (L-IPA). Sulfafenazolo (inibitore di CYP2C) ha evidenziato un valore di IC50 pari a 47,2 μM, suggerendo dunque la necessità di effettuare ulteriori studi volti a verificare la specificità di substrato (L-H), ad esempio utilizzando altri inibitori selettivi per tale sottofamiglia come l’ibuprofene o il diclofenac. I metodi in luminescenza messi a punto permettono di analizzare un numero elevato di campioni in tempi brevi, di monitorare più di un’isoforma contemporaneamente nella stessa piastra e sono caratterizzati da una buona sensibilità, confermata dai valori di LOD ottenuti: 0,2 e 0,11 nM per L-H e L-IPA, rispettivamente. I risultati ottenuti dunque possono costituire un ottimo punto di partenza per poter applicare la tecnologia di tali saggi in studi relativi alle specie di interesse veterinario con vantaggi di costi e tempi di realizzazione delle analisi

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EPrint type:Ph.D. thesis
Tutor:Capolongo, Francesca
Ph.D. course:Ciclo 22 > Scuole per il 22simo ciclo > SCIENZE VETERINARIE > SANITA' PUBBLICA E PATOLOGIA COMPARATA
Data di deposito della tesi:UNSPECIFIED
Anno di Pubblicazione:25 January 2010
Key Words:citocromo P450; HPLC; cinetica enzimatica; validazione; inquinamento ambientale; trattamenti illeciti; metodi luminescenza
Settori scientifico-disciplinari MIUR:Area 07 - Scienze agrarie e veterinarie > VET/07 Farmacologia e tossicologia veterinaria
Struttura di riferimento:Dipartimenti > pre 2012 - Dipartimento di Sanità pubblica, Patologia comparata ed Igiene veterinaria
Codice ID:2453
Depositato il:28 Oct 2010 17:12
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