Singularities of nevirapine metabolism: from sex-dependent differences to idiosyncratic toxicity

Marinho, Aline T.; Miranda, Joana P.; Caixas, Umbelina; Charneira, Catarina; Gonçalves-Dias, Clara; Marques, M. Matilde; Monteiro, Emília C.; Antunes, Alexandra M. M.; Pereira, Sofia A.

doi:10.1080/03602532.2019.1577891

Cited by 9 publications

(7 citation statements)

References 133 publications

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“…These metabolites have distinct abilities to form covalent adducts with proteins, which can either lead to toxic effects [36,37] or undergo detoxification via glutathione conjugation [6]. Thus, NVP reactive metabolites can also directly fine-tune glutathione availability and dynamics [7].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the resort to spheroid or to multicompartment membrane bioreactor cultures further improved HLC maturation and functionality [5]. Indeed, three-dimensional (3D) culture systems allow higher cell-to-cell and cell-to-matrix contact, as well as nutrient and oxygen gradients and cell polarization [6][7][8][9]. These features are essential for the functional specialization of hepatocytes, which can be of enormous impact when employing in vitro systems to investigate susceptibility to drug-induced adverse-reactions [1], such as those induced by the hepatotoxic drug nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor [6].…”

Section: Introductionmentioning

confidence: 99%

“…As mentioned above, NVP is an antiretroviral drug associated with severe hepatotoxicity, through the formation of reactive metabolites ( Figure 1) [7]. NVP biotransformation comprises the formation of multiple Phase I metabolites (2-, 3-, 8-, and 12-OH-NVP, and 4-carboxy-NVP) that undergo subsequent Phase II glucuronidation or undergo detoxification trough GSH conjugation ( Figure 1) [14].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, NVP induces CYP2B6 and CYP3A4 [16], whereas its Phase I metabolite, 2-OH-NVP ( Figure 1), induces SULT1A1 [6]. Therefore, due to its bioactivation, and subsequent detoxification and toxicity mechanisms, NVP has been shown to be a relevant drug for investigating drug metabolism and bioactivation competence of in vitro models [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence and Glutathiolomic Profile of a Human Hepatocyte-Like Cell 3D Model

Cipriano

Pinheiro

Sequeira

et al. 2020

IJMS

Self Cite

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The need for competent in vitro liver models for toxicological assessment persists. The differentiation of stem cells into hepatocyte-like cells (HLC) has been adopted due to its human origin and availability. Our aim was to study the usefulness of an in vitro 3D model of mesenchymal stem cell-derived HLCs. 3D spheroids (3D-HLC) or monolayer (2D-HLC) cultures of HLCs were treated with the hepatotoxic drug nevirapine (NVP) for 3 and 10 days followed by analyses of Phase I and II metabolites, biotransformation enzymes and drug transporters involved in NVP disposition. To ascertain the toxic effects of NVP and its major metabolites, the changes in the glutathione net flux were also investigated. Phase I enzymes were induced in both systems yielding all known correspondent NVP metabolites. However, 3D-HLCs showed higher biocompetence in producing Phase II NVP metabolites and upregulating Phase II enzymes and MRP7. Accordingly, NVP-exposure led to decreased glutathione availability and alterations in the intracellular dynamics disfavoring free reduced glutathione and glutathionylated protein pools. Overall, these results demonstrate the adequacy of the 3D-HLC model for studying the bioactivation/metabolism of NVP representing a further step to unveil toxicity mechanisms associated with glutathione net flux changes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence and Glutathiolomic Profile of a Human Hepatocyte-Like Cell 3D Model

Cipriano

Pinheiro

Sequeira

et al. 2020

IJMS

Self Cite

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“…The interplay of complex host and viral genetic differences is likely to play a huge role in determining pathologic outcomes in PWH. For example, differences in HIV strains/variants (Rao et al 2013 ) and human/host genetic variability (Proudnikov et al 2012 ), pharmacokinetics (Kuhlman et al 1996 ; Eap et al 2002 ; Elkader and Sproule 2005 ; Kharasch 2017 ; Kringen et al 2017 ), and sex (Zubieta et al 2002 ; Taylor and Davies 2010 ; Venuto et al 2014 ; Marinho et al 2019 ) all contribute to variability in responsiveness. The following subsections will focus on key factors affecting opioid and HIV comorbidity.…”

Section: Matters Needing Further Consideration In Opioid and Hiv Comomentioning

confidence: 99%

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Fitting

McRae

Hauser

2020

J Neuroimmune Pharmacol

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With the current national opioid crisis, it is critical to examine the mechanisms underlying pathophysiologic interactions between human immunodeficiency virus (HIV) and opioids in the central nervous system (CNS). Recent advances in experimental models, methodology, and our understanding of disease processes at the molecular and cellular levels reveal opioid-HIV interactions with increasing clarity. However, despite the substantial new insight, the unique impact of opioids on the severity, progression, and prognosis of neuroHIV and HIV-associated neurocognitive disorders (HAND) are not fully understood. In this review, we explore, in detail, what is currently known about mechanisms underlying opioid interactions with HIV, with emphasis on individual HIV-1-expressed gene products at the molecular, cellular and systems levels. Furthermore, we review preclinical and clinical studies with a focus on key considerations when addressing questions of whether opioid-HIV interactive pathogenesis results in unique structural or functional deficits not seen with either disease alone. These considerations include, understanding the combined consequences of HIV-1 genetic variants, host variants, and μ-opioid receptor (MOR) and HIV chemokine co-receptor interactions on the comorbidity. Lastly, we present topics that need to be considered in the future to better understand the unique contributions of opioids to the pathophysiology of neuroHIV. Graphical Abstract Blood-brain barrier and the neurovascular unit. With HIV and opiate co-exposure (represented below the dotted line), there is breakdown of tight junction proteins and increased leakage of paracellular compounds into the brain. Despite this, opiate exposure selectively increases the expression of some efflux transporters, thereby restricting brain penetration of specific drugs.

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Evaluation of antiviral effect and toxicity of total flavonoids extracted from Robinia pseudoacacia cv. idaho

Guo¹,

Wan²,

Niu³

et al. 2019

Biomedicine & Pharmacotherapy

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Singularities of nevirapine metabolism: from sex-dependent differences to idiosyncratic toxicity

Cited by 9 publications

References 133 publications

Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence and Glutathiolomic Profile of a Human Hepatocyte-Like Cell 3D Model

Nevirapine Biotransformation Insights: An Integrated In Vitro Approach Unveils the Biocompetence and Glutathiolomic Profile of a Human Hepatocyte-Like Cell 3D Model

Opioid and neuroHIV Comorbidity – Current and Future Perspectives

Evaluation of antiviral effect and toxicity of total flavonoids extracted from Robinia pseudoacacia cv. idaho

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