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https://www.readbyqxmd.com/read/28427998/nitric-oxide-regulated-proteolysis-of-human-cyp2b6-via-the-ubiquitin-proteasome-system
#1
Choon-Myung Lee, Shweta Tripathi, Edward T Morgan
We showed previously that rat cytochrome P450 CYP2B1 undergoes NO-dependent proteasomal degradation in response to inflammatory stimuli, and that the related human enzyme CYP2B6 is also down-regulated by NO in primary human hepatocytes. To investigate the mechanism of CYP2B6 down-regulation, we made several cell lines (HeLa and HuH7 cells) in which native CYP2B6 or CYP2B6 with a C-terminal V5 tag (CYP2B6V5) are expressed from a lentiviral vector with a cytomegalovirus promoter. Native CYP2B6 protein was rapidly down-regulated in HeLa cells within 3h of treatment with the NO donor (Z)-1-[2-(2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate, while its mRNA level was not down-regulated...
April 17, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28368100/halogen-%C3%AF-interactions-in-the-cytochrome-p450-active-site-structural-insights-into-human-cyp2b6-substrate-selectivity
#2
Manish B Shah, Jingbao Liu, Qinghai Zhang, C David Stout, James R Halpert
Numerous cytochrome P450 (CYP) 2B6 substrates including drugs and environmental chemicals are halogenated. To assess the role of halogen-π bonds in substrate selectivity and orientation in the active site, structures of four CYP2B6 monoterpenoid complexes were solved by X-ray crystallography. Bornyl bromide exhibited dual orientations in the active site with the predominant orientation revealing a bromine-π bond with the Phe108 side chain. Bornane demonstrated two orientations with equal occupancy; in both, the C2 atom that bears the bromine in bornyl bromide was displaced by more than 2...
April 6, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28287454/am-2201-inhibits-multiple-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#3
Ju-Hyun Kim, Soon-Sang Kwon, Tae Yeon Kong, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography-tandem mass spectrometry to investigate drug interaction potentials of AM-2201...
March 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28275870/synthesis-of-short-retinoidal-amides-related-to-fenretinide-antioxidant-activities-and-differentiation-inducing-ability
#4
Maria Anzaldi, Maurizio Viale, Chiara Macciò, Patrizio Castagnola, Valentina Oliveri, Camillo Rosano, Alessandro Balbi
PURPOSE: By a scaffold shortening strategy, a small series of retinoidal amides fenretinide (4-HPR) analogs have been synthesized from α, β-ionones and tested for their antiproliferative and differentiating activities, and antioxidant effect. METHODS: The antiproliferative activity and triggering of apoptosis of our short retinoids were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4'-6-diamidino-2-phenylindole staining and microscope evaluation after 3- or 6-day exposure, while their differentiating activity was established by the analysis of the expression of the CD11b marker of differentiation in treated HL60 target cells and by the superoxide production assayed colorimetrically by the nitro blue tetrazolium-reducing activity assay...
March 9, 2017: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/28145050/cytochrome-2b6-polymorphism-and-efavirenz-induced-central-nervous-system-symptoms-a-substudy-of-the-anrs-alize-trial
#5
S Gallien, V Journot, M-A Loriot, H Sauvageon, P Morlat, J Reynes, V Reliquet, G Chêne, J-M Molina
OBJECTIVES: Single nucleotide polymorphisms in the cytochrome P450 (CYP) 2B6 gene have been associated with high interindividual variation in efavirenz pharmacokinetics. However, clinical data on the relationship of CYP2B6 polymorphisms with the occurrence of efavirenz-induced central nervous system (CNS) symptoms are limited. METHODS: We analysed four polymorphisms in the CYP2B6 (516 G>T), CYP3A5 (6986 A>G) and ATP-binding cassette, sub-family B, member 1 (ABCB1) (2677 G>T/A and 3435 C>T) genes in HIV-infected adults virologically suppressed on a protease inhibitor-based regimen who switched to a regimen containing emtricitabine, didanosine and efavirenz in the setting of the ANRS ALIZE trial...
February 1, 2017: HIV Medicine
https://www.readbyqxmd.com/read/28119166/in-vitro-toxicological-evaluation-of-ncs-382-a-high-affinity-antagonist-of-%C3%AE-hydroxybutyrate-ghb-binding
#6
K R Vogel, G R Ainslie, J-B Roullet, A McConnell, K M Gibson
γ-Hydroxybutyric acid (GHB), a minor metabolite of the inhibitory neurotransmitter GABA, can accumulate to significant concentrations in the heritable disorder of GABA degradation, succinic semialdehyde dehydrogenase (SSADH) deficiency (SSADHD). Moreover, GHB may be employed in therapeutic settings (treatment of narcolepsy), as well as instances of illicit activity, including acquaintance sexual assault and the induction of euphoria. High-affinity binding sites for GHB in the brain have been identified, although the absolute identity of these receptors remains unclear...
January 22, 2017: Toxicology in Vitro: An International Journal Published in Association with BIBRA
https://www.readbyqxmd.com/read/27994733/identification-synthesis-and-biological-evaluation-of-the-major-human-metabolite-of-nlrp3-inflammasome-inhibitor-mcc950
#7
Manohar Salla, Mark S Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E Croker, Janet C Reid, Jong Min Baek, Paul V Bernhardt, Elizabeth M J Gillam, Matthew A Cooper, Avril A B Robertson
MCC950 is an orally bioavailable small molecule inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that exhibits remarkable activity in multiple models of inflammatory disease. Incubation of MCC950 with human liver microsomes, and subsequent analysis by HPLC-MS/MS, revealed a major metabolite, where hydroxylation of MCC950 had occurred on the 1,2,3,5,6,7-hexahydro-s-indacene moiety. Three possible regioisomers were synthesized, and coelution using HPLC-MS/MS confirmed the structure of the metabolite...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27978469/highly-sensitive-lc-ms-ms-methods-for-the-determination-of-seven-human-cyp450-activities-using-small-oral-doses-of-probe-drugs-in-human
#8
Alexia Grangeon, Sophie Gravel, Fleur Gaudette, Jacques Turgeon, Veronique Michaud
Cocktails composed of several Cytochrome P450 (CYP450)-selective probe drugs have been shown of value to characterize in vivo drug-metabolism activities. Our objective was to develop and validate highly sensitive and selective LC-MS/MS assays allowing the determination of seven major human CYP450 isoenzyme activities following administration of low oral doses of a modified CYP450 probe-drug cocktail in patients. The seven-drug cocktail was composed of caffeine, bupropion, tolbutamide, omeprazole, dextromethorphan, midazolam (all administered concomitantly) and chlorzoxazone (administered separately) to phenotype for CYP1A2, 2B6, 2C9, 2C19, 2D6, 3A4/5 and 2E1, respectively...
January 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/27904432/corrections-of-frequencies-of-cytochrome-p450-2b6-and-2c8-allelic-variants-in-the-mozambican-population
#9
COMMENT
Mostafa Saadat
No abstract text is available yet for this article.
September 2016: Malaysian Journal of Medical Sciences: MJMS
https://www.readbyqxmd.com/read/27860311/single-heteroatom-substitutions-in-the-efavirenz-oxazinone-ring-impact-metabolism-by-cyp2b6
#10
Philip M Cox, Namandjé N Bumpus
Previously, we observed that the oxazinone ring is important for cytochrome P450 2B6 (CYP2B6) activity toward efavirenz ((4S)-6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one), a CYP2B6 substrate used to treat HIV. To further understand the structural characteristics of efavirenz that render it a CYP2B6 substrate, we tested the importance of each heteroatom of the oxazinone ring. We assembled a panel of five analogues: 6-chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-2-methyl-4-(trifluoromethyl)-2H-3,1-benzoxazine (1), (4S)-6-chloro-4-[(1E)-2-cyclopropylethenyl]-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (2), (4S)-6-chloro-4-(2-cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (3), 6-chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinolinone (4), and 6-chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]dioxin-2-one (5)...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27853934/evaluation-of-in-vitro-cytochrome-p450-inhibition-and-in-vitro-fate-of-structurally-diverse-n-oxide-metabolites-case-studies-with-clozapine-levofloxacin-roflumilast-voriconazole-and-zopiclone
#11
Poonam Giri, Sneha Naidu, Nirmal Patel, Harilal Patel, Nuggehally R Srinivas
BACKGROUND AND OBJECTIVES: The role of metabolite(s) to elicit potential clinical drug-drug interaction (DDI) via cytochrome P450 enzymes (CYP) is gaining momentum. In this context, the role of N-oxides for in vitro CYP inhibition has not been evaluated. The objectives of this study were: (a) to examine in vitro CYP inhibition of N-oxides of clozapine, levofloxacin, roflumilast, voriconazole and zopiclone in a tiered approach and (b) evaluate in vitro fate of aforementioned N-oxides examined in recombinant CYPs, human microsomes and hepatocytes...
November 16, 2016: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/27842484/strong-induction-of-cytochrome-p450-1a-3a-but-not-p450-2b-in-cultured-hepatocytes-from-common-marmosets-and-cynomolgus-monkeys-by-typical-human-p450-inducing-agents
#12
Shotaro Uehara, Yasuhiro Uno, Takako Suzuki, Takashi Inoue, Masahiro Utoh, Erika Sasaki, Hiroshi Yamazaki
BACKGROUND: Common marmosets (Callithrix jacchus) and cynomolgus monkeys (Macaca fascicularis) are used as non-human primate models in preclinical studies for drug development. OBJECTIVE: The assessment of P450 induction in hepatocytes from marmosets and cynomolgus monkeys was performed using typical P450 inducers. METHODS: Induction of cytochrome P450 1-4 family enzymes was analyzed in two lots of cultured hepatocytes from common marmosets and cynomolgus monkeys after 24-h treatment with typical human P450 inducing agents by real-time reverse transcription-polymerase chain reaction...
November 14, 2016: Drug Metabolism Letters
https://www.readbyqxmd.com/read/27779789/role-of-cytochrome-p450-2b6-pharmacogenomics-in-determining-efavirenz-mediated-central-nervous-system-toxicity-treatment-outcomes-and-dosage-adjustments-in-patients-with-human-immunodeficiency-virus-infection
#13
REVIEW
Teresa T Vo, Sheeba Varghese Gupta
For treatment-naive patients with human immunodeficiency virus infection, efavirenz (EFV), together with tenofovir and emtricitabine, was once widely prescribed given its efficacy and ease of administration in a combination pill. However, the high rate of central nervous system (CNS) toxicities from EFV prompted the U.S. Department of Health and Human Services to move the EFV-based regimen from the recommended to the alternative category. For patients who do meet the criteria for newer recommended antiretroviral treatments, EFV is a viable option and often the mainstay of treatment outside the United States because newer antiretroviral treatments are more expensive...
December 2016: Pharmacotherapy
https://www.readbyqxmd.com/read/27766562/a-physiologically-based-pharmacokinetic-model-to-predict-human-fetal-exposure-for-a-drug-metabolized-by-several-cyp450-pathways
#14
Maïlys De Sousa Mendes, Gabrielle Lui, Yi Zheng, Claire Pressiat, Deborah Hirt, Elodie Valade, Naïm Bouazza, Frantz Foissac, Stephane Blanche, Jean-Marc Treluyer, Saik Urien, Sihem Benaboud
BACKGROUND: Pregnant women and their fetuses are exposed to numerous drugs; however, they are orphan populations with respect to the safety and efficacy of drugs. Therefore, the prediction of maternal and fetal drug exposure prior to administration would be highly useful. METHODS: A physiologically-based pharmacokinetic (PBPK) model for nevirapine, which is metabolized by the cytochrome P450 (CYP) 3A4, 2B6 and 2D6 pathways, was developed to predict maternal and fetal pharmacokinetics (PK)...
May 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27758707/new-psychoactive-substances-3-methoxyphencyclidine-3-meo-pcp-and-3-methoxyrolicyclidine-3-meo-pcpy-metabolic-fate-elucidated-with-rat-urine-and-human-liver-preparations-and-their-detectability-in-urine-by-gc-ms-lc-high-resolution-msn-and-lc-high-resolution
#15
Julian A Michely, Sascha K Manier, Achim T Caspar, Simon D Brandt, Jason Wallach, Hans H Maurer
3-Methoxyphencyclidine (3-MeO-PCP) and 3-methoxyrolicyclidine (3-MeO-PCPy) are two new psychoactive substances (NPS). The aims of the present study were the elucidation of their metabolic fate in rat and pooled human liver microsomes (pHLM), the identification of the cytochrome P450 (CYP) isoenzymes involved, and the detectability using standard urine screening approaches (SUSA) after intake of common users' doses using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-multi-stage mass spectrometry (LC-MSn), and liquid chromatography-high-resolution tandem mass spectrometry (LC-HR-MS/MS)...
October 18, 2016: Current Neuropharmacology
https://www.readbyqxmd.com/read/27749294/a-case-of-delayed-emergence-after-propofol-anesthesia-genetic-analysis
#16
Hiroshi Yonekura, Norie Murayama, Hiroshi Yamazaki, Kazuya Sobue
This case report describes a 71-year-old woman who experienced unusual delayed emergence from propofol, which lasted for 3 hours and resulted in admission to the intensive care unit. Because genetic variations of propofol-metabolizing enzymes are proposed to be causal factors, we explored genetic polymorphisms of cytochrome P450 2B6 (CYP2B6) and uridine 5'-diphospho-glucuronosyltransferase 1A9 (UGT1A9). Suggested high-risk factors (advanced age, CYP2B6 516 G/T, and UGT1A9 I399 C/C) were observed in this case of delayed propofol metabolism...
December 1, 2016: A & A Case Reports
https://www.readbyqxmd.com/read/27636207/a-case-of-3-4-dimethoxyamphetamine-3-4-dma-and-3-4-methylenedioxymethamphetamine-mdma-toxicity-with-possible-metabolic-interaction
#17
Michael A Darracq, Stephen L Thornton, Alicia B Minns, Roy R Gerona
We present a case of "ecstasy" ingestion revealing 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-dimethoxyamphetamine (3,4-DMA) and absence of cytochrome P450 (CYP)-2D6 MDMA metabolites. CASE REPORT: A 19-year-old presented following a seizure. Initial vital signs were normal. Laboratories were normal with the exception of sodium 127 mEq/L and urine drugs of abuse screen positive for amphetamines. Twelve hours later, serum sodium was 114 mEq/L and a second seizure occurred. After receiving hypertonic saline (3%), the patient had improvement in mental status and admitted to taking "ecstasy" at a rave prior to her initial presentation...
November 2016: Journal of Psychoactive Drugs
https://www.readbyqxmd.com/read/27625140/roles-of-human-cyp2a6-and-monkey-cyp2a24-and-2a26-cytochrome-p450-enzymes-in-the-oxidation-of-2-5-2-5-tetrachlorobiphenyl
#18
Tsutomu Shimada, Kensaku Kakimoto, Shigeo Takenaka, Nobuyuki Koga, Shotaro Uehara, Norie Murayama, Hiroshi Yamazaki, Donghak Kim, F Peter Guengerich, Masayuki Komori
2,5,2',5'-Tetrachlorobiphenyl (TCB) induced type I binding spectra with cytochrome P450 (P450) 2A6 and 2A13, with Ks values of 9.4 and 0.51 µM, respectively. However, CYP2A6 oxidized 2,5,2',5'-TCB to form 4-hydroxylated products at a much higher rate (∼1.0 minute(-1)) than CYP2A13 (∼0.02 minute(-1)) based on analysis by liquid chromatography-tandem mass spectrometry. Formation of 4-hydroxy-2,5,2',5'-TCB by CYP2A6 was greater than that of 3-hydroxy-2,5,2',5'-TCB and three other hydroxylated products. Several human P450 enzymes, including CYP1A1, 1A2, 1B1, 2B6, 2D6, 2E1, 2C9, and 3A4, did not show any detectable activities in oxidizing 2,5,2',5'-TCB...
December 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27616666/gene-expression-study-of-phase-i-and-ii-metabolizing-enzymes-in-rptec-tert1-cell-line-application-in-in-vitro-nephrotoxicity-prediction
#19
Heta Shah, Manish Patel, Neeta Shrivastava
1. The phase I and II metabolizing enzymes of kidneys play an important role in the metabolism of xenobiotic as well as endogenous compounds and proximal tubules of kidney constitute high concentration of these metabolizing enzymes compared with the other parts. 2. It has been shown previously that differential enzyme expression among human and rodent/non-rodent species can be a roadblock in drug discovery and development process. Currently, proximal tubule cell lines of human origin such as RPTEC/TERT1 and HK-2 are used to understand the pathophysiology of kidney diseases, therapeutic efficacy of drugs, and nephrotoxicity of compounds...
October 3, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27600044/inhibition-of-cytochrome-p450-2b6-activity-by-voriconazole-profiled-using-efavirenz-disposition-in-healthy-volunteers
#20
Zeruesenay Desta, Ingrid F Metzger, Nancy Thong, Jessica B L Lu, John T Callaghan, Todd C Skaar, David A Flockhart, Raymond E Galinsky
Cytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration...
November 2016: Antimicrobial Agents and Chemotherapy
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