Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death

Heck, Carley J S; Seneviratne, Herana Kamal; Bumpus, Namandjé N.

doi:10.1021/acs.jmedchem.9b01990

Cited by 10 publications

(14 citation statements)

References 52 publications

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“…The same group also reported data obtained from a proteomics study performed with HepG2 cells cultured for one week with 819 μM NVP, in which nearly 40% of the differentially expressed proteins were mitochondrial proteins, providing evidence of NVP interfering with mitochondria in this model [ 77 ]. Conversely, we have shown that NVP lacks mitochondrial toxicity in another human hepatoma cell line, Hep3B, though the treatment in question (10–50 µM) lasted only a few hours [ 78 ]. Differences in the expression of drug-metabolizing genes between HepG2 and Hep3B cells may explain this discrepancy.…”

Section: Mechanisms Of Nnrti-induced Liver Injurymentioning

confidence: 99%

NNRTI and Liver Damage: Evidence of Their Association and the Mechanisms Involved

Benedicto

Fuster-Martínez

Tosca

et al. 2021

Cells

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Due to the improved effectiveness and safety of combined antiretroviral therapy, human immunodeficiency virus (HIV) infection has become a manageable, chronic condition rather than a mortal disease. However, HIV patients are at increased risk of experiencing non-AIDS-defining illnesses, with liver-related injury standing out as one of the leading causes of death among these patients. In addition to more HIV-specific processes, such as antiretroviral drug-related toxicity and direct injury to the liver by the virus itself, its pathogenesis is related to conditions that are also common in the general population, such as alcoholic and non-alcoholic fatty liver disease, viral hepatitis, and ageing. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of combined anti-HIV treatment due to their unique antiviral activity, high specificity, and acceptable toxicity. While first-generation NNRTIs (nevirapine and efavirenz) have been related largely to liver toxicity, those belonging to the second generation (etravirine, rilpivirine and doravirine) seem to be generally safe for the liver. Indeed, there is preclinical evidence of rilpivirine being hepatoprotective in different models of liver injury, independently of the presence of HIV. The present study aims to review the mechanisms by which currently available anti-HIV drugs belonging to the NNRTI family may participate in the development of liver disease.

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Section: Mechanisms Of Nnrti-induced Liver Injurymentioning

confidence: 99%

NNRTI and Liver Damage: Evidence of Their Association and the Mechanisms Involved

Benedicto

Fuster-Martínez

Tosca

et al. 2021

Cells

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“…NVP is metabolized by cytochrome P450, resulting in the formation of four mono-oxygenated metabolites, of which 12-hydroxy-NVP (12-OHNVP) is associated with hepatotoxicity and skin toxicity [78,79]. In a recent study using primary mouse hepatocytes, supra-therapeutic concentrations of NVP-induced cell death, while a version of the drug in which the twelfth-position had been trideuterated (12-D3NVP) exerted a lesser effect in comparison to NVP [80]. In contrast, in another study assessing the toxicity of two-day exposure of primary hepatocytes from five human donors to NVP or ritonavir (RTV), the former inhibited EIF2 signaling and was predicted to suppress downstream ATF4and CHOP-related apoptotic pathways (revealed by analysis of transcriptomic data) and PDI and heat shock responses.…”

Section: Nnrtismentioning

confidence: 99%

Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment

Gruevska

Moragrega

Cossarizza

et al. 2021

Cells

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Due to medical advances over the past few decades, human immunodeficiency virus (HIV) infection, once a devastatingly mortal pandemic, has become a manageable chronic condition. However, available antiretroviral treatments (cART) cannot fully restore immune health and, consequently, a number of inflammation-associated and/or immunodeficiency complications have manifested themselves in treated HIV-infected patients. Among these chronic, non-AIDS (acquired immune deficiency syndrome)-related conditions, liver disease is one of the deadliest, proving to be fatal for 15–17% of these individuals. Aside from the presence of liver-related comorbidities, including metabolic disturbances and co-infections, HIV itself and the adverse effects of cART are the main factors that contribute to hepatic cell injury, inflammation, and fibrosis. Among the molecular mechanisms that are activated in the liver during HIV infection, apoptotic cell death of hepatocytes stands out as a key pathogenic player. In this review, we will discuss the evidence and potential mechanisms involved in the apoptosis of hepatocytes induced by HIV, HIV-encoded proteins, or cART. Some antiretroviral drugs, especially the older generation, can induce apoptosis of hepatic cells, which occurs through a variety of mechanisms, such as mitochondrial dysfunction, increased production of reactive oxygen species (ROS), and induction of endoplasmic reticulum (ER) stress and unfolded protein response (UPR), all of which ultimately lead to caspase activation and cell death.

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“…Primarily, CYP2B6 and CYP3A4 metabolize NVP to 2-hydroxynevirapine (OH-NVP), 3-OH-NVP, 8-OH-NVP, and 12-OH-NVP. However, reactive metabolite, 12-sulphoxynevirapine (12-SUL-NVP) from the SULTs biotransformation of 12-OH-NVP is also known to be a major cause of NVP Hypersensitivity (20,21). Highly polymorphic sulfotransferase 1A1 (SULT1A1), is marked with differences in their variants (1A1*1, 1A1*2 and 1A1*3) with signi cantly reduced enzyme activity (22).…”

Section: Introductionmentioning

confidence: 99%

Cyp2b6 and Sult1a1 Single Nucleotide Polymorphism: Implication for Nevirapine-based Hiv Therapy Among Ghanaians

Prah

Asiedu-Gyekye

Nartey

et al. 2023

Preprint

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Background Nevirapine is used in many developing countries for the management of HIV-1 patients. Despite its usefulness, hypersensitivity reaction is a common complication that accounts for patients defaulting during therapy in Ghana. Genetic variations in drug-metabolizing enzymes have been implicated in reported adverse drug reactions observed in patients on nevirapine regimen. The study determined genotypic frequencies of specific CYP2B6 and SULT1A1 variants and their association with nevirapine hypersensitivity among persons living with HIV in the Ghanaian population.Methods An unmatched case-control study was conducted in a tertiary health facility in Ghana. Baseline clinical data were recorded from the patients’ folder. Genomic DNA (gDNA) samples were genotyped for CYP2B6*18 (c.983T > C) and SULT1A1*2 (c.638G > A) using Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP).Results Mean age of the patients was 38 ± 9.47 years with the majority 77.1% (54/70) of the participants being females. For CYP2B6*18 (c.983T > C) genotype frequencies, T/T and T/C were 94.3% (66/70) and 5.7% (4/70) respectively while for SULT1A1*2 (c.638G > A) genotype frequencies, G/G, G/A, and A/A were 61.4% (43/70), 34.3% (24/70) and 4.3% (3/70) respectively. The prevalence of CYP2B6*18 (c.983T > C) and SULT1A1*2 (c.638G > A) minor allele were 2.9% (4/140) and 21.4% (30/140) respectively among the study participants.Conclusion Extensive metabolizer genotypes for CYP2B6*18 (c.983T > C) and SULT1A1*2 (c.638G > A) were more common than the intermediate and poor metabolizer genotype. However, CYP2B6 983C/C representing poor metabolizers of CYP2B6*18 (c.983T > C) were not detected among the study population. Genetic polymorphism of CYP2B6*18 (c.983T > C) and SULT1A1*2 (c.638G > A) were not associated with nevirapine hypersensitivity. However, these variants may contribute to differential variations of other drug responses among the Ghanaian population.

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Twelfth-Position Deuteration of Nevirapine Reduces 12-Hydroxy-Nevirapine Formation and Nevirapine-Induced Hepatocyte Death

Cited by 10 publications

References 52 publications

NNRTI and Liver Damage: Evidence of Their Association and the Mechanisms Involved

NNRTI and Liver Damage: Evidence of Their Association and the Mechanisms Involved

Apoptosis of Hepatocytes: Relevance for HIV-Infected Patients under Treatment

Cyp2b6 and Sult1a1 Single Nucleotide Polymorphism: Implication for Nevirapine-based Hiv Therapy Among Ghanaians

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