Nevirapine modulation of paraoxonase-1 in the liver: An in vitro three-model approach

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• 作者：Aline T. Marinho^a ; ^{aline.marinho@fcm.unl.pt" class="auth_mail" title="E-mail the corresponding author} ; Clara G. Dias^a ; ^{clara.dias@fcm.unl.pt" class="auth_mail" title="E-mail the corresponding author} ; Pedro F. Pinheiro^b ; ^c ; ^{pfpinheiro@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Ana Rita Lemos^a ; ^{ar.lemos@campus.fct.unl.pt" class="auth_mail" title="E-mail the corresponding author} ; Alexandra M.M. Antunes^c ; ^{alexandra.antunes@tecnico.ulisboa.pt" class="auth_mail" title="E-mail the corresponding author} ; M. Matilde Marques^c ; ^{matilde.marques@tecnico.ulisboa.pt" class="auth_mail" title="E-mail the corresponding author} ; Emí ; lia C. Monteiro^a ; ^{emilia.monteiro@fcm.unl.pt" class="auth_mail" title="E-mail the corresponding author} ; Joana P. Miranda^b ; ¹ ; ^{jmiranda@ff.ulisboa.pt" class="auth_mail" title="E-mail the corresponding author} ; Sofia A. Pereira^a ; ¹ ; ^{sofia.pereira@fcm.unl.pt" class="auth_mail" title="E-mail the corresponding author}
• 关键词：2D ; two-dimensional ; 3D ; three-dimensional ; 5-HETEL ; 5-hydroxy-eicosatetraenoic acid lactone ; AHLs ; acylhomoserine lactones ; AhR ; arylhydrocarbon receptor ; ANOVA ; analysis of variance ; AREase ; arylesterase activity ; BSA ; bovine serum albumin ; CYP ; cytochrome P450 ; DMSO ; dimethyl sulfoxide ; EROD ; ethoxyresorufin-O-deethylation ; FBS ; foetal bovine serum ; Hcy ; homocysteine ; HcyTL ; homocysteine-thiolactone ; HEPES ; 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid ; HIV ; human immunodeficiency virus
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2016
• 出版时间：20 January 2016
• 年：2016
• 卷：82
• 期：Complete
• 页码：147-153
• 全文大小：473 K

文摘

Nevirapine is associated with severe hepatotoxicity, through the formation of reactive metabolites. Paraoxonase-1 (PON-1) is a promiscuous enzyme involved in the metabolism of xeno- and endobiotics and proposed as a biomarker of hepatotoxicity. The aim of this work was to explore the effects of nevirapine and its phase I metabolites, 2-hydroxy-nevirapine and 12-hydroxy-nevirapine, on PON-1 activities.

Material and methods

2D and 3D primary cultures of rat hepatocytes, and also HepG2 2D cell cultures, were exposed to nevirapine, 2-hydroxy-nevirapine, and 12-hydroxy-nevirapine. The paraoxonase (POase), arylesterase (AREase) and lactonase (LACase) activities of PON-1 were quantified.

Results

Effects of nevirapine and its metabolites were only observed in the 3D cell model. Both nevirapine and 12-hydroxy-nevirapine increased POase (p < 0.05, p < 0.01) and LACase activities (p < 0.05, p < 0.001). The AREase activity was increased only upon 12-hydroxy-nevirapine exposure (p < 0.01). These modulatory effects were observed at 300 μM concentrations of nevirapine and 12-hydroxy-nevirapine.

Conclusions

The formation of 12-hydroxy-nevirapine seems to be the main factor responsible for the increase of PON-1 activities induced by nevirapine exposure. This effect was only observed in the 3D model, suggesting that an in vivo-like system is necessary for this modulation to occur. The present data suggest that the 3D model is a more suitable in vitro model than the conventional ones to explore drug effects on PON-1.