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Drug Metabolism and Disposition: the Biological Fate of Chemicals

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https://www.readbyqxmd.com/read/29025858/histone-modifications-regulate-the-developmental-expression-of-human-hepatic-ugt1a1
#1
Ya-Li Nie, Xiang-Guang Meng, Jing-Yang Liu, Liang Yan, Pei Wang, Hong-Zheng Bi, Quan-Cheng Kan, Li-Rong Zhang
Human UDP-glucuronosyltransferase 1A1 (UGT1A1) is a unique enzyme involved in bilirubin conjugation. We previously characterized the hepatic expression of transcription factors affecting UGT1A1 expression during development. Accordingly, in this study, we characterized the ontogenetic expression of hepatic UGT1A1 from the perspective of epigenetic regulation. We observed significant histone-3-lysine-4 dimethylation (H3K4me2) enrichment in the adult liver and histone-3-lysine-27 trimethylation (H3K27me3) enrichment in the fetal liver, indicating that dynamic alterations of histone methylation were associated with ontogenetic UGT1A1 expression...
October 12, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29021351/metabolic-epoxidation-is-a-critical-step-for-the-development-of-benzbromarone-induced-hepatotoxicity
#2
Hui Wang, Ying Peng, Tingjian Zhang, Qunsheng Lan, Huimin Zhao, Wenbao Wang, Yufei Zhao, Xu Wang, Jianxin Pang, Shaojie Wang, Jiang Zheng
Benzbromarone (BBR) is effective in the treatment of gout but can also cause fatal hepatic failure in clinic. Our early studies demonstrated that CYP3A catalyzed the biotransformation of BBR to epoxide intermediate(s) which reacted with sulfur nucleophiles of protein to form protein covalent binding both in vitro and in vivo. The present study attempted to define the correlation between metabolic epoxidation and hepatotoxicity of BBR by manipulating the structure of BBR. We rationally designed and synthesized three halogenated BBR derivatives (6-F-, Cl-, or Br-BBR) to decrease the potential for P450-mediated metabolic activation...
October 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29018033/expression-and-functional-characterization-of-breast-cancer-associated-cytochrome-p450-4z1-in-saccharomyces-cerevisiae
#3
Matthew G McDonald, Sutapa Ray, Clara J Amorosi, Katherine A Sitko, John P Kowalski, Lorela Paco, Abhinav Nath, Byron M Gallis, Rheem A Totah, Maitreya J Dunham, Douglas M Fowler, Allan E Rettie
CYP4Z1 is an 'orphan' P450 enzyme that has provoked interest because of its hypothesized role in breast cancer through formation of the signaling molecule 20-HETE. We expressed human CYP4Z1 in Saccharomyces cerevisiae and evaluated its catalytic capabilities towards arachidonic and lauric acids (AA and LA). Specific and sensitive mass spectrometry assays enabled discrimination of the regioselectivity of hydroxylation of these two fatty acids. CYP4Z1 generated 7-, 8-, 9-, 10- and 11-hydroxy LA, while the 12-hydroxy metabolite was not detected...
October 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29018032/n-acetyltransferase-2-genotype-dependent-n-acetylation-of-hydralazine-in-human-hepatocytes
#4
Cecily E Allen, Mark A Doll, David W Hein
Hydralazine is used in treatment of essential hypertension and is under investigation for epigenetic therapy in the treatment of neoplastic and renal diseases. N-acetyltransferase 2 (NAT2) exhibits a common genetic polymorphism in human populations. Following recombinant expression in yeast, human NAT2 exhibited an apparent Km (20.1 ± 8.8 μM) for hydralazine over 20-fold lower than the apparent Km (456 ± 57 μM) for recombinant human NAT1 (p=0.0016). The apparent Vmax for recombinant human NAT1 (72.2 ± 17...
October 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28986476/colistin-is-substrate-of-the-carnitine-organic-cation-transporter-2-octn2-slc22a5
#5
Michele Visentin, Zhibo Gai, Angelo Torozi, Christian Hiller, Gerd A Kullak-Ublick
Colistin is a polycation antibiotic used for the treatment of multidrug-resistance (MDR) gram-negative infections; nevertheless, its use is often limited by the high incidence of renal damage. The mechanism underlying colistin-induced nephrotoxicity is not known, but perhaps related to its accumulation in the renal cortex upon extensive reabsorption from the nascent urine. Because little is known about the membrane transport of colistin, the purpose of the present study was to characterize better the transport system involved in colistin renal handling by using HEK293 cells stably transfected with the main organic cation transporters expressed at the apical membrane of the proximal tubule...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28986475/pediatric-cytochrome-p450-activity-alterations-in-nonalcoholic-steatohepatitis
#6
Hui Li, Canet J Mark, John D Clarke, Dean Billheimer, Stavra A Xanthakos, Joel E Lavine, Robert P Erickson, Nathan J Cherrington
Variable drug responses(VDRs) are dependent upon individual variation in the activity of drug-metabolizing enzymes including cytochrome P450s(CYPs). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis(NASH) has been identified as a source of significant inter-individual variation in hepatic drug metabolism. Compared to adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYPs in children and adolescents...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28986474/digging-deeper-into-cyp3a-testosterone-metabolism-kinetic-regio-and-stereoselectivity-differences-between-cyp3a4-5-and-cyp3a7
#7
Sylvie E Kandel, Lyrialle W Han, Qingcheng Mao, Jed N Lampe
The metabolism of testosterone to 6β-hydroxytestosterone is a commonly used assay to evaluate human CYP3A enzyme activities. However, previous reports have indicated that CYP3A7 also produces 2α-hydroxytestosterone, and that a 2α-hydroxytestosterone:6β-hydroxytestosterone ratio may be a unique biomarker of the isozyme's activity. Until now, the full metabolite and kinetic profile for testosterone hydroxylation by CYP3A7 has not been fully examined. To this end, we performed a complete kinetic analysis of the 6β-hydroxytestosterone, 2α-hydroxytestosterone and 2β-hydroxytestosterone metabolites for recombinant SupersomeTM CYP3A4, 3A5, and 3A7 enzymes and monitored metabolism in fetal and adult human liver microsomes for comparison...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28986473/mouse-red-blood-cell-mediated-rare-xenobiotic-phosphorylation-of-a-drug-molecule-not-intended-to-be-a-kinase-substrate
#8
Chungang Gu, Shenghua Wen, Peter Doig, Eric Gangl, Xiaolan Zheng, Yanjun Wang, Jeffrey W Johannes
Phosphorylation of xenobiotics is rare, probably due to a strong evolutionary pressure against it. This rarity may have attracted more attention recently, owing to intentionally designed kinase-substrate analogs which depend on kinase-catalyzed activation to form phosphorylated active drugs. We report a rare phosphorylated metabolite observed unexpectedly in mouse plasma samples after an oral dose of a Tankyrase inhibitor that was not intended to be a kinase substrate, i.e. (S)-2-(4-(6-(3,4-dimethylpiperazin-1-yl)-4-methylpyridin-3-yl)phenyl)-8-(hydroxymethyl)quinazolin-4(3H)-one (AZ2381)...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28978661/studies-on-para-methoxymethamphetamine-pmma-metabolite-pattern-and-influence-of-cyp2d6-genetics-in-human-liver-microsomes-and-authentic-samples-from-fatal-pmma-intoxications
#9
Merete Vevelstad, Elisabeth Leere Oiestad, Elisabeth Nerem, Marianne Arnestad, Inger Lise Bogen
Para-methoxymethamphetamine (PMMA) has caused numerous fatal poisonings worldwide and appears to be more toxic than other ring-substituted amphetamines. Systemic metabolism is suggested to be important for PMMA neurotoxicity, possibly through activation of minor catechol metabolites to neurotoxic conjugates. The aim of this study was to examine the metabolism of PMMA in humans, and for this purpose we used human liver microsomes (HLM) and blood samples from three cases of fatal PMMA intoxication. We also examined the impact of CYP2D6 genetics on PMMA metabolism using genotyped HLM isolated from CYP2D6 poor, population average and ultrarapid metabolizers...
October 4, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28939687/rna-seq-profiling-of-intestinal-expression-of-xenobiotic-processing-genes-in-germ-free-mice
#10
Zidong Donna Fu, Felcy P Selwyn, Julia Yue Cui, Curtis D Klaassen
Intestinal bacteria can affect xenobiotic metabolism through both direct bacterial enzyme-catalyzed modification of the xenobiotics and indirect alterations of the expression of host genes. In order to determine the effect of the lack of intestinal bacteria on the expression of xenobiotic-processing genes (XPGs) of the host intestine, the mRNA profiles of 303 XPGs were characterized by high-throughput RNA-sequencing in four sections of the intestine and compared to that in the liver from adult male conventional (CV) and germ-free (GF) mice...
September 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28939686/species-specific-involvement-of-aldehyde-oxidase-and-xanthine-oxidase-in-the-metabolism-of-the-pyrimidine-containing-mglu5-negative-allosteric-modulator-vu0424238-auglurant
#11
Rachel D Crouch, Anna L Blobaum, Andrew S Felts, P Jeffrey Conn, Craig W Lindsley
Aldehyde oxidase (AO) and xanthine oxidase (XO) are molybdo-flavoenzymes that catalyze oxidation of aromatic azaheterocycles. Differences in AO activity have been reported among various species including rat, human, and monkey. Herein we report a species difference in the enzymes responsible for metabolism of mGlu5 NAM VU0424238 (VU238, auglurant). Hepatic S9 incubations with AO and XO specific inhibitors hydralazine and allopurinol indicated that rat and cynomolgus monkey both oxidized VU238 to the 6-oxopyrimidine metabolite M1 via an AO-mediated pathway, whereas secondary oxidation to the 2,6-dioxopyrimidine metabolite M2 was mediated predominantly by AO in monkey and XO in rat...
September 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28935657/use-of-hybrid-capillary-tube-setup-on-400mhz-nmr-for-quantitation-of-crucial-low-quantity-metabolites-using-asicco-signal
#12
Ranjeet Tiwari, Deepak Ahire, Hemantha Kumar, Sarmistha Sinha, Siddheshwar Kisan Chauthe, Murali Subramanian, Ramaswamy Iyer, Ramakanth Sarabu, Lakshmi Kant Bajpai
Metabolites of new chemical entities can influence safety and efficacy of a molecule and often times need to be quantified in preclinical studies. However, synthetic standards of metabolites are very rarely available in early discovery. Alternate approaches such as bio-synthesis needs to be explored to generate these metabolites. Assessing the quantity and purity of these small amounts of metabolites with a non-destructive analytical procedure becomes crucial. Quantitative nuclear magnetic resonance (qNMR) becomes the method of choice for these samples...
September 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28935656/the-effect-of-chronic-treatment-with-lurasidone-on-rat-liver-cytochrome-p450-expression-and-activity-in-the-chronic-mild-stress-cms-model-of-depression
#13
Marta Kot, Anna Haduch, Mariusz Papp, Władysława Anna Daniel
Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression...
September 21, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28928138/progressive-and-preferential-cellular-accumulation-of-hydrophobic-bile-acids-induced-by-cholestatic-drugs-is-associated-with-inhibition-of-their-amidation-and-sulfation
#14
Ahmad Sharanek, Audrey Burban, Lydie Humbert, Christiane Guguen-Guillouzo, Dominique Rainteau, Andre Guillouzo
Drug-induced intrahepatic cholestasis is characterized by cellular accumulation of bile acids (BA) whose mechanisms remain poorly understood. The present study aimed to analyze early and progressive alterations of BA profiles induced by cyclosporine A, chlorpromazine, troglitazone, tolcapone, trovafloxacin and tacrolimus after 4h, 24h and 6 daily treatments of differentiated HepaRG cells. In BA-free medium the potent cholestatic drugs, cyclosporine A, chlorpromazine and troglitazone, reduced endogenous BA synthesis after 24h, while the rarely cholestatic drugs, tolcapone, trovafloxacin and tacrolimus, reduced BA synthesis only after 6 days...
September 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28928137/recovery-of-cyp3a-phenotype-following-kidney-transplantation
#15
Kristine Hole, Elisabet Storset, Ane Olastuen, Tore Haslemo, Grete Birkeland Kro, Karsten Midtvedt, Anders Asberg, Espen Molden
End-stage renal disease (ESRD) impairs drug metabolism via cytochrome P450 (CYP) 3A. However, it is unclear whether CYP3A activity recovers following kidney transplantation. Therefore, the aim of this study was to evaluate the change in CYP3A activity measured as 4β-hydroxycholesterol (4βOHC) concentration after kidney transplantation. In total, data from 58 renal transplant recipients with 550 prospective 4βOHC measurements were included in the study. One sample per patient was collected before transplantation, and 2-12 samples per patient were collected 1-82 days after transplantation...
September 19, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28916530/elucidation-of-the-impact-of-p-glycoprotein-and-breast-cancer-resistance-protein-on-the-brain-distribution-of-catechol-o-methyltransferase-inhibitors
#16
Joana Bicker, Ana Fortuna, Gilberto Alves, Patricio Soares-da-Silva, Amilcar Falcao
P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are clinically important efflux transporters that act cooperatively at the blood-brain barrier, limiting the entry of several drugs into the CNS and affecting their pharmacokinetics, therapeutic efficacy and safety. In the present study, the interactions of catechol-O-methyltransferase (COMT) inhibitors (BIA 9-1059, BIA 9-1079, entacapone, nebicapone, opicapone and tolcapone) with P-gp and BCRP were investigated in order to determine the contribution of these transporters in their access to the brain...
September 15, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28912253/physiologically-based-pharmacokinetic-model-predictions-of-panobinostat-lbh589-as-a-victim-and-perpetrator-of-drug-drug-interactions
#17
Heidi J Einolf, Wen Lin, Christina S Won, Lai Wang, Helen Gu, Dung Yu Chun, Handan He, James B Mangold
Panobinostat (Farydak®) is an orally active hydroxamic acid derived histone deacetylase inhibitor for the treatment of relapsed/refractory multiple myeloma. Based upon recombinant cytochrome P450 (CYP) kinetic analyses in vitro, panobinostat oxidative metabolism in human liver microsomes was found to be primarily mediated by CYP3A4 with lower contributions by CYP2D6 and CYP2C19. Panobinostat was also shown to be an in vitro reversible and time-dependent inhibitor of CYP3A4/5, and a reversible inhibitor of CYP2D6 and CYP2C19...
September 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28904007/synthetic-analogs-of-curcumin-modulate-the-function-of-multidrug-resistance-linked-abc-transporter-abcg2
#18
Megumi Murakami, Shinobu Ohnuma, Michihiro Fukuda, Eduardo E Chufan, Katsuyoshi Kudoh, Keigo Kanehara, Norihiko Sugisawa, Masaharu Ishida, Takeshi Naitoh, Hiroyuki Shibata, Yoshiharu Iwabuchi, Suresh V Ambudkar, Michiaki Unno
Multidrug resistance (MDR) caused by the overexpression of ATP-binding cassette (ABC) transporters in cancer cells is a major obstacle in cancer chemotherapy. Previous studies have shown that curcumin, a natural product and a dietary constituent of turmeric, inhibits the function of MDR-related ABC transporters, including ABCB1, ABCC1, and especially ABCG2. However, the limited bioavailability of curcumin prevents its use for modulation of the function of these transporters in the clinical setting. In this study, we investigated the effects of twenty-four synthetic curcumin analogs with increased bioavailability on the transport function of ABCG2...
September 13, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28887366/clearance-prediction-methodology-needs-fundamental-improvement-trends-common-to-rat-and-human-hepatocytes-microsomes-and-implications-for-experimental-methodology
#19
Francesca Leanne Wood, James Brian Houston, David Hallifax
Although prediction of clearance using hepatocytes and liver microsomes has long played a decisive role in drug discovery, it is widely acknowledged that reliably accurate prediction is not yet achievable despite the predominance of hepatically cleared drugs. Physiologically mechanistic methodology tends to underpredict clearance by several-fold and empirical correction of this bias is confounded by imprecision across drugs. Understanding of the causes of prediction uncertainty has been slow, possibly reflecting poor resolution of variables associated with donor source and experimental methods, particularly for the human situation...
September 8, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28864749/wuzhi-tablet-schisandra-sphenanthera-extract-is-a-promising-tacrolimus-sparing-agent-for-renal-transplant-recipients-who-are-cyp3a5-expressers-a-two-phase-prospective-study
#20
Jia-Li Li, Siyang Chen, Xiaoling Qin, Qian Fu, Huichang Bi, Yu Zhang, Xueding Wang, Longshan Liu, Changxi Wang, Min Huang
Tacrolimus is a potent but expensive first-line immunosuppressant, thus solutions to reduce tacrolimus consumption while maintain therapeutic level are in urgent need. A two-phase prospective study was conducted to assess the efficacy of an ethanolic extraction preparation of Schisandra sphenanthera (Wuzhi tablet) as a tacrolimus-sparing agent in renal transplant recipients who were high-dose tacrolimus consumers (CYP3A5*1 allele carriers, CYP3A5 expressers). A total of twelve patients were included in the Part I study...
September 1, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
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