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In Vitro Activation of Cytochrome P450 46A1 (CYP46A1) by Efavirenz-Related Compounds.
Mast N, Verwilst P, Wilkey CJ, Guengerich FP, Pikuleva IA
(2020) J Med Chem 63: 6477-6488
MeSH Terms: Alkynes, Allosteric Site, Benzoxazines, Catalytic Domain, Cholesterol, Cholesterol 24-Hydroxylase, Cyclopropanes, Cytochrome P-450 CYP3A Inducers, Humans, Hydroxylation, In Vitro Techniques, Pharmaceutical Preparations, Protein Conformation
Show Abstract · Added March 3, 2020
Cytochrome P450 46A1 (CYP46A1) is a central nervous system-specific enzyme, which catalyzes cholesterol 24-hydroxylation. Currently CYP46A1 is being evaluated in a clinical trial for activation by small doses of the anti-HIV drug efavirenz. Eight efavirenz-related compounds were investigated for CYP46A1 activation in vitro, induction of a CYP46A1 spectral response, spectral values, interaction with the P450 allosteric sites, and a model of binding to the enzyme active site. We gained insight into structure-activity relationships of efavirenz for CYP46A1 activation and found that the investigated efavirenz primary metabolites are stronger and better activators of CYP46A1 than efavirenz. We also established that CYP46A1 is activated by racemates and that a conformational-selection mechanism is operative in CYP46A1. The results suggest structural modifications of efavirenz to further increase CYP46A1 activation without inhibition at high compound concentrations. It is possible that not only efavirenz but its metabolites activate CYP46A1 in vivo.
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13 MeSH Terms
Race/Ethnicity and the Pharmacogenetics of Reported Suicidality With Efavirenz Among Clinical Trials Participants.
Mollan KR, Tierney C, Hellwege JN, Eron JJ, Hudgens MG, Gulick RM, Haubrich R, Sax PE, Campbell TB, Daar ES, Robertson KR, Ventura D, Ma Q, Edwards DRV, Haas DW, AIDS Clinical Trials Group
(2017) J Infect Dis 216: 554-564
MeSH Terms: Adult, Alkynes, Anti-HIV Agents, Benzoxazines, Continental Population Groups, Cyclopropanes, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, Ethnic Groups, Female, Gene Frequency, Genotype, HIV Infections, Humans, Male, Pharmacogenetics, Polymorphism, Single Nucleotide, Proportional Hazards Models, Risk Factors, Suicidal Ideation, Suicide, Treatment Outcome
Show Abstract · Added March 3, 2020
Background - We examined associations between suicidality and genotypes that predict plasma efavirenz exposure among AIDS Clinical Trials Group study participants in the United States.
Methods - Four clinical trials randomly assigned treatment-naive participants to efavirenz-containing regimens; suicidality was defined as reported suicidal ideation or attempted or completed suicide. Genotypes that predict plasma efavirenz exposure were defined by CYP2B6 and CYP2A6 polymorphisms. Associations were evaluated with weighted Cox proportional hazards models stratified by race/ethnicity. Additional analyses adjusted for genetic ancestry and selected covariates.
Results - Among 1833 participants, suicidality was documented in 41 in exposed analyses, and 34 in on-treatment analyses. In unadjusted analyses based on 12 genotype levels, suicidality increased per level in exposed (hazard ratio, 1.11; 95% confidence interval, .96-1.27) and on-treatment 1.16; 1.01-1.34) analyses. In the on-treatment analysis, the association was strongest among white but nearly null among black participants. Considering 3 metabolizer levels (extensive, intermediate and slow), slow metabolizers were at increased risk. Results were similar after baseline covariate-adjustment for genetic ancestry, sex, age, weight, injection drug use history, and psychiatric history or recent psychoactive medication.
Conclusions - Genotypes that predict higher plasma efavirenz exposure were associated with increased risk of suicidality. Strength of association varied by race/ethnicity.
© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.
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Brief Report: Weight Gain in Persons With HIV Switched From Efavirenz-Based to Integrase Strand Transfer Inhibitor-Based Regimens.
Norwood J, Turner M, Bofill C, Rebeiro P, Shepherd B, Bebawy S, Hulgan T, Raffanti S, Haas DW, Sterling TR, Koethe JR
(2017) J Acquir Immune Defic Syndr 76: 527-531
MeSH Terms: Adult, Alkynes, Benzoxazines, Cohort Studies, Cyclopropanes, Female, HIV Infections, HIV Integrase Inhibitors, Humans, Male, Middle Aged, Retrospective Studies, Reverse Transcriptase Inhibitors, Weight Gain
Show Abstract · Added March 14, 2018
BACKGROUND - With the introduction of integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy, persons living with HIV have a potent new treatment option. Recently, providers at our large treatment clinic noted weight gain in several patients who switched from efavirenz/tenofovir disoproxil fumarate/emtricitabine (EFV/TDF/FTC) to dolutegravir/abacavir/lamivudine (DTG/ABC/3TC). In this study, we evaluated weight change in patients with sustained virologic suppression who switched from EFV/TDF/FTC to an INSTI-containing regimen.
METHODS - We performed a retrospective observational cohort study among adults on EFV/TDF/FTC for at least 2 years who had virologic suppression. We assessed weight change over 18 months in patients who switched from EFV/TDF/FTC to an INSTI-containing regimen or a protease inhibitor (PI)-containing regimen versus those on EFV/TDF/FTC over the same period. In a subgroup analysis, we compared patients switched to DTG/ABC/3TC versus raltegravir- or elvitegravir-containing regimens.
RESULTS - A total of 495 patients were included: 136 who switched from EFV/TDF/FTC to an INSTI-containing regimen and 34 switched to a PI-containing regimen. Patients switched to an INSTI-containing regimen gained an average of 2.9 kg at 18 months compared with 0.9 kg among those continued on EFV/TDF/FTC (P = 0.003), whereas those switched to a PI regimen gained 0.7 kg (P = 0.81). Among INSTI regimens, those switched to DTG/ABC/3TC gained the most weight at 18 months (5.3 kg, P = 0.001 compared with EFV/TDF/FTC).
CONCLUSION - Adults living with HIV with viral suppression gained significantly more weight after switching from daily, fixed-dose EFV/TDF/FTC to an INSTI-based regimen compared with those remaining on EFV/TDF/FTC. This weight gain was greatest among patients switching to DTG/ABC/3TC.
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cytochrome P450 46A1 (CYP46A1) activation by neuroactive compounds.
Mast N, Anderson KW, Johnson KM, Phan TTN, Guengerich FP, Pikuleva IA
(2017) J Biol Chem 292: 12934-12946
MeSH Terms: Acetylcholine, Alkynes, Allosteric Regulation, Amino Acid Substitution, Anti-HIV Agents, Aspartic Acid, Benzoxazines, Binding Sites, Biocatalysis, Cholesterol 24-Hydroxylase, Cyclopropanes, Deuterium Exchange Measurement, Enzyme Activation, Glutamic Acid, Ligands, Models, Molecular, Molecular Docking Simulation, Mutagenesis, Site-Directed, Mutation, Nerve Tissue Proteins, Peptide Fragments, Protein Conformation, Recombinant Fusion Proteins, gamma-Aminobutyric Acid
Show Abstract · Added March 14, 2018
Cytochrome P450 46A1 (CYP46A1, cholesterol 24-hydroxylase) is the enzyme responsible for the majority of cholesterol elimination from the brain. Previously, we found that the anti-HIV drug efavirenz (EFV) can pharmacologically activate CYP46A1 in mice. Herein, we investigated whether CYP46A1 could also be activated by endogenous compounds, including major neurotransmitters. experiments with purified recombinant CYP46A1 indicated that CYP46A1 is activated by l-glutamate (l-Glu), l-aspartate, γ-aminobutyric acid, and acetylcholine, with l-Glu eliciting the highest increase (3-fold) in CYP46A1-mediated cholesterol 24-hydroxylation. We also found that l-Glu and other activating neurotransmitters bind to the same site on the CYP46A1 surface, which differs from the EFV-binding site. The other principal differences between EFV and l-Glu in CYP46A1 activation include an apparent lack of l-Glu binding to the P450 active site and different pathways of signal transduction from the allosteric site to the active site. EFV and l-Glu similarly increased the CYP46A1 , the rate of the "fast" phase of the enzyme reduction by the redox partner NADPH-cytochrome P450 oxidoreductase, and the amount of P450 reduced. Spectral titrations with cholesterol, in the presence of EFV or l-Glu, suggest that water displacement from the heme iron can be affected in activator-bound CYP46A1. Moreover, EFV and l-Glu synergistically activated CYP46A1. Collectively, our data, along with those from previous cell culture and studies by others, suggest that l-Glu-induced CYP46A1 activation is of physiological relevance.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
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Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis.
Toutounchian JJ, Pagadala J, Miller DD, Baudry J, Park F, Chaum E, Morales-Tirado , Yates CR
(2017) Mol Pharmacol 91: 1-13
MeSH Terms: Animals, Benzoxazines, Cell Movement, Cell Proliferation, Disease Models, Animal, Endothelial Cells, Focal Adhesion Protein-Tyrosine Kinases, Humans, Mice, Inbred C57BL, Models, Biological, Oxygen, Paxillin, Retinal Neovascularization, Signal Transduction, Small Molecule Libraries, Vascular Endothelial Growth Factor A, src-Family Kinases
Show Abstract · Added June 11, 2018
Targeting vascular endothelial growth factor (VEGF) is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor-induced ischemic retinopathy in the murine oxygen-induced retinopathy model could be inhibited. In this study, we demonstrated that VEGF-dependent activation of the Src/FAK/paxillin signalsome is required for human retinal endothelial cell migration and proliferation. Specifically, the disruption of focal adhesion kinase (FAK) and paxillin interactions using the small molecule JP-153 inhibited Src-dependent phosphorylation of paxillin (Y118) and downstream activation of Akt (S473), resulting in reduced migration and proliferation of retinal endothelial cells stimulated with VEGF. However, this effect did not prevent the initial activation of either Src or FAK. Furthermore, topical application of a JP-153-loaded microemulsion affected the hallmark features of pathologic retinal angiogenesis, reducing neovascular tuft formation and increased avascular area, in a dose-dependent manner. In conclusion, our results suggest that using small molecules to modulate the focal adhesion protein paxillin is an effective strategy for treating pathologic retinal neovascularization. To our knowledge, this is the first paradigm validating modulation of paxillin to inhibit angiogenesis. As such, we have identified and developed a novel class of small molecules aimed at targeting focal adhesion protein interactions that are essential for pathologic neovascularization in the eye.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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The metabolic and cardiovascular consequences of obesity in persons with HIV on long-term antiretroviral therapy.
Koethe JR, Grome H, Jenkins CA, Kalams SA, Sterling TR
(2016) AIDS 30: 83-91
MeSH Terms: Adult, Alkynes, Anti-Retroviral Agents, Benzoxazines, Cardiovascular Diseases, Cohort Studies, Cyclopropanes, Emtricitabine, Female, HIV Infections, Humans, Male, Metabolic Diseases, Middle Aged, Obesity, Risk Assessment, Tenofovir
Show Abstract · Added February 17, 2016
OBJECTIVE - This study assessed the effect of obesity on metabolic and cardiovascular disease risk factors in HIV-infected adults on antiretroviral therapy with sustained virologic suppression.
DESIGN - Observational, comparative cohort study with three group-matched arms: 35 nonobese and 35 obese HIV-infected persons on efavirenz, tenofovir and emtricitabine with plasma HIV-1 RNA  less than  50  copies/ml for more than 2 years, and 30 obese HIV-uninfected controls. Patients did not have diabetes or known cardiovascular disease.
METHODS - We compared glucose tolerance, serum lipids, brachial artery flow-mediated dilation, carotid intima-media thickness, and soluble inflammatory and vascular adhesion markers between nonobese and obese HIV-infected patients, and between obese HIV-infected and HIV-uninfected patients, using Wilcoxon rank-sum tests and multivariate linear regression.
RESULTS - The cohort was 52% men and 48% nonwhite. Nonobese and obese HIV-infected patients did not differ by clinical or demographic characteristics. Obese HIV-uninfected controls were younger than obese HIV-infected patients and less likely to smoke (P < 0.03 for both). Among HIV-infected patients, obesity was associated with greater insulin release, lower insulin sensitivity, and higher serum high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 1 levels (P < 0.001), but similar lipid profiles, sCD14, sCD163, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and carotid intima-media thickness and flow mediated dilation. In contrast, Obese HIV-infected patients had adverse lipid changes, and greater circulating intercellular adhesion molecule 1, vascular cell adhesion molecule 1 and sCD14, compared with obese HIV-uninfected controls after adjusting for age and other factors.
CONCLUSION - Obesity impairs glucose metabolism and contributes to circulating high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 1 levels, but has few additive effects on dyslipidemia and endothelial activation, in Obese HIV-infected adults on long-term antiretroviral therapy.
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Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study.
Luetkemeyer AF, Rosenkranz SL, Lu D, Grinsztejn B, Sanchez J, Ssemmanda M, Sanne I, McIlleron H, Havlir DV, Haas DW, Adult AIDS Clinical Trials Group A5221 and A5243 Study Teams
(2015) Clin Infect Dis 60: 1860-3
MeSH Terms: Alkynes, Antitubercular Agents, Arylamine N-Acetyltransferase, Benzoxazines, Cyclopropanes, Cytochrome P-450 CYP2B6, Female, Genotype, HIV Infections, Humans, Male, Peru, Pharmacogenetics, Rifampin, South Africa, Tuberculosis, Uganda
Show Abstract · Added March 13, 2015
In STRIDE, slow metabolizer CYP2B6 and NAT2 genotypes were each associated with increased plasma efavirenz concentrations during antituberculosis therapy. Concentrations were greater on therapy than off therapy in 58% with CYP2B6 and 93% with NAT2 slow metabolizer genotypes. Individuals with slow metabolizer genotypes in both genes had markedly elevated concentrations.
© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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Pharmacogenetics of plasma efavirenz exposure in HIV-infected adults and children in South Africa.
Sinxadi PZ, Leger PD, McIlleron HM, Smith PJ, Dave JA, Levitt NS, Maartens G, Haas DW
(2015) Br J Clin Pharmacol 80: 146-56
MeSH Terms: Adolescent, Adult, African Continental Ancestry Group, Alkynes, Anti-HIV Agents, Benzoxazines, Child, Child, Preschool, Cyclopropanes, Cytochrome P-450 CYP2B6, Female, Genotype, HIV Infections, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, South Africa, Young Adult
Show Abstract · Added March 13, 2015
AIMS - Genetic factors, notably CYP2B6 516G→T [rs3745274] and 983T→C [rs28399499], explain much of the interindividual variability in efavirenz pharmacokinetics, but data from Africa are limited. We characterized relationships between genetic polymorphisms and plasma efavirenz concentrations in HIV-infected Black South African adults and children.
METHODS - Steady-state mid-dosing interval efavirenz concentrations were measured. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport, including ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3.
RESULTS - Among 113 participants (59 adults and 54 children), minor allele frequencies for CYP2B6 516G→T, 983T→C, and 15582C→T [rs4803419] were 0.36, 0.07, and 0.09, respectively. Based on composite CYP2B6 15582/516/983 genotype, there were 33 extensive metabolizer, 62 intermediate metabolizer and 18 slow metabolizer genotypes. Median (IQR) mid-dose efavirenz concentrations were 1.44 (1.21-1.93) µg ml(-1), 2.08 (1.68-2.94) µg ml(-1) and 7.26 (4.82-8.34) µg ml(-1) for extensive, intermediate and slow metabolizers, respectively. In univariate analyses, a model that included composite genotype best predicted efavirenz concentrations (β = 0.28, 95% CI 0.21, 0.35, P = 2.4 × 10(-11)). Among individual CYP2B6 polymorphisms, 516G→T best predicted efavirenz concentrations (β = 0.22, 95% CI 0.13, 0.30, P = 1.27 × 10(-6)). There was also associations with 983T→C (β = 0.27, 95% CI 0.10, 0.44, P = 0.002) and 15582C→T (β = 0.11, 95% CI 0.01, 0.22, P = 0.04). Associations were consistent in adults and children. No other polymorphisms were independently associated with efavirenz concentrations.
CONCLUSIONS - Composite CYP2B6 genotype based on CYP2B6 516G→T, 983T→C, and 15582C→T best described efavirenz exposure in HIV-infected Black South African adults and children.
© 2015 The British Pharmacological Society.
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Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols.
Lehmann DS, Ribaudo HJ, Daar ES, Gulick RM, Haubrich RH, Robbins GK, de Bakker PI, Haas DW, McLaren PJ
(2015) Pharmacogenet Genomics 25: 51-9
MeSH Terms: Acquired Immunodeficiency Syndrome, Alkynes, Anti-HIV Agents, Benzoxazines, Cyclopropanes, Dideoxynucleosides, Drug Therapy, Combination, Genome-Wide Association Study, HIV Infections, HIV-1, Humans, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Treatment Outcome
Show Abstract · Added March 13, 2015
BACKGROUND - Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols.
PARTICIPANTS AND METHODS - Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n = 786) regimens in ACTG protocols 384, A5142, A5095, and A5202.
RESULTS - Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P < 5 × 10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition.
CONCLUSION - No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.
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Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection.
Dooley KE, Denti P, Martinson N, Cohn S, Mashabela F, Hoffmann J, Haas DW, Hull J, Msandiwa R, Castel S, Wiesner L, Chaisson RE, McIlleron H, TSHEPISO Study Team
(2015) J Infect Dis 211: 197-205
MeSH Terms: Adolescent, Adult, Alkynes, Anti-HIV Agents, Benzoxazines, Cohort Studies, Coinfection, Cyclopropanes, Female, HIV Infections, HIV-1, Humans, Plasma, Pregnancy, Pregnancy Complications, Infectious, Prospective Studies, South Africa, Tuberculosis, Viral Load, Young Adult
Show Abstract · Added March 13, 2015
BACKGROUND - Pregnancy and tuberculosis treatment or prophylaxis can affect efavirenz pharmacokinetics, maternal human immunodeficiency virus type 1 (HIV-1) treatment outcomes, and mother-to-child transmission (MTCT) risk.
METHODS - We evaluated a prospective cohort of pregnant, HIV-infected women with and without tuberculosis in Soweto, South Africa. Pharmacokinetic sampling was performed at gestation week 37 and during the postpartum period. Efavirenz trough concentrations (Cmin) were predicted using population pharmacokinetic models. HIV-viral load was measured at delivery for mothers and at 6 weeks of age for infants.
RESULTS - Ninety-seven women participated; 44 had tuberculosis. Median efavirenz Cmin during pregnancy was 1.35 µg/mL (interquartile range [IQR], 0.90-2.07 µg/mL; 27% had an efavirenz Cmin of < 1 µg/mL), compared with a median postpartum value of 2.00 µg/mL (IQR, 1.40-3.59 µg/mL; 13% had an efavirenz Cmin of < 1 µg/mL). A total of 72% of pregnant women with extensive CYP2B6 genotypes had an efavirenz Cmin of <1 µg/mL. Rifampin did not reduce the efavirenz Cmin. Isoniazid (for prophylaxis or treatment), though, reduced the rate of efavirenz clearance. At delivery, median durations of ART were 13 weeks (IQR, 9-18 weeks) and 21 weeks (IQR, 13-64 weeks) for women with and those without tuberculosis, respectively; 55% and 83%, respectively, had a viral load of <20 copies/mL (P = .021). There was 1 case of MTCT.
CONCLUSIONS - Pregnancy increased the risk of low efavirenz concentrations, but MTCT was rare. A detectable HIV-viral load at delivery was more common among pregnant women with tuberculosis, in whom ART was generally initiated later.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
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20 MeSH Terms