当前位置： SCI文献检索 > Drug Metabolism and Pharmacokinetics期刊下所有文献 > Mechanism-based inactivation of cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus constituents.

Mechanism-based inactivation of cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus constituents.

Abstract：

:  Human cytochrome P450 CYP2A6 and CYP2A13 catalyze nicotine metabolisms and mediate activation of tobacco-specific carcinogens including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we found rhinacanthins A, B, and C isolated from Rhinacanthus nasutus potentially inhibited coumarin 7-hydroxylation mediated by reconstituted purified recombinant CYP2A6 and CYP2A13. Rhinacanthins A-C are mechanism-based inactivators of CYP2A6 and CYP2A13 as they cause concentration, time and NADPH-dependent inhibition. Among the three rhinacanthins, rhinacanthin-B possessed highest inhibitory potency against CYP2A13 with apparent KI and kinact of 0.16 µM and 0.1 min(-1), respectively, while values of 0.44 µM and 0.12 min(-1) were found against CYP2A6. Rhinacanthin-C had least inhibition potency, with apparent KI and kinact of 0.97 µM and 0.07 min(-1) for CYP2A6, respectively, and values of 1.68 µM and 0.05 min(-1) for CYP2A13. Rhinacanthin-A inhibited CYP2A6 and CYP2A13 with apparent KI values of 0.69 and 0.42 µM, respectively and apparent kinact of 0.18 and 0.06 min(-1), respectively. The inhibition of both enzymes by rhinacanthins A-C could not be prevented by addition of trapping agents or reversed by dialysis or potassium ferricyanide. These findings demonstrated that rhinacanthins A-C, which are 1,4-naphthoquinone derivatives, irreversibly inhibited CYP2A6 and CYP2A13 in a mechanism-based inhibition mode.

journal_name

Drug Metab Pharmacokinet

journal_title

Drug metabolism and pharmacokinetics

authors

Pouyfung P,Prasopthum A,Sarapusit S,Srisook E,Rongnoparut P

doi

10.2133/dmpk.dmpk-13-rg-048

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

75-82

issue

1

eissn

1347-4367

issn

1880-0920

pii

DN/JST.JSTAGE/dmpk/DMPK-13-RG-048

journal_volume

29

pub_type

杂志文章

相关文献

Drug Metabolism and Pharmacokinetics文献大全
  • Dihydrofolate reductase gene intronic 19-bp deletion polymorphisms in a Japanese population.

    abstract：:Dihydrofolate reductase gene (DHFR) 19-bp deletion polymorphisms result in varied DHFR enzymatic activity affecting the risk for preterm delivery, spina bifida, and the efficacy of methotrexate (MTX). Ethnic differences in DHFR 19-bp polymorphisms may be responsible for the divergent findings in previous genetic studi...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.dmpk-10-sc-036

    authors： Hayashi H,Horino M,Morishita M,Tazoe Y,Tsuboi S,Matsuyama T,Kosuge K,Yamada H,Tsuji D,Inoue K,Itoh K

    更新日期：2010-01-01 00:00:00

  • Non-synonymous genetic variants of flavin-containing monooxygenase 3 (FMO3) in cynomolgus macaques.

    abstract：:Polymorphic human flavin-containing monooxygenase (FMO) 3 is an important drug-metabolizing enzyme for nitrogen- or sulfur-containing compounds. Cynomolgus macaques, a non-human primate species widely used in drug metabolism studies, have corresponding FMO3 molecular and enzymatic similarities to humans; however, gene...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2018.09.001

    authors： Uno Y,Shimizu M,Yoda H,Origuchi Y,Yamazaki H

    更新日期：2019-02-01 00:00:00

  • P-glycoprotein limits the brain penetration of olopatadine hydrochloride, H1-receptor antagonist.

    abstract：:Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-g...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.23.106

    authors： Mimura N,Nagata Y,Kuwabara T,Kubo N,Fuse E

    更新日期：2008-01-01 00:00:00

  • A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy.

    abstract：:We have recently found that the frequency of OATP-C*15 is significantly higher in patients who experienced myopathy after receiving pravastatin or atorvastatin than in patients without myopathy. However, there were two patients who experienced pravastatin-induced myopathy despite the fact that they did not possess OAT...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.19.453

    authors： Morimoto K,Oishi T,Ueda S,Ueda M,Hosokawa M,Chiba K

    更新日期：2004-12-01 00:00:00

  • The utility of CYP3A activity endogenous markers for evaluating drug-drug interaction between sildenafil and CYP3A inhibitors in healthy subjects.

    abstract：:Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An ...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2020.11.003

    authors： Lee S,Kim AH,Yoon S,Lee J,Lee Y,Ji SC,Yoon SH,Lee S,Yu KS,Jang IJ,Cho JY

    更新日期：2021-02-01 00:00:00

  • Valproic acid transport in the choriocarcinoma placenta cell line JEG-3 proceeds independently of the proton-dependent transporters MCT1 and MCT4.

    abstract：:Medication therapy is the first line of treatment in the management of epilepsy. Fetal exposure to valproic acid (VPA), an antiepileptic drug, poses an elevated risk of teratogenicity in early pregnancy. Some studies have reported that monocarboxylate transporters (MCTs) may be involved in the placental transport of V...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2018.03.004

    authors： Ishiguro Y,Furugen A,Narumi K,Nishimura A,Hirano T,Kobayashi M,Iseki K

    更新日期：2018-12-01 00:00:00

  • Organic cation transporter Octn1-mediated uptake of food-derived antioxidant ergothioneine into infiltrating macrophages during intestinal inflammation in mice.

    abstract：:OCTN1/SLC22A4 is expressed on apical membranes of small intestine, and is involved in gastrointestinal absorption of its substrates, including the food-derived antioxidant ergothioneine (ERGO). ERGO concentration in circulating blood of patients with inflammatory bowel disease (Crohn's disease) is lower than that in h...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2015.02.003

    authors： Shimizu T,Masuo Y,Takahashi S,Nakamichi N,Kato Y

    更新日期：2015-06-01 00:00:00

  • A novel approach to the prediction of drug-drug interactions in humans based on the serum incubation method.

    abstract：:A novel method for the prediction of drug-drug interaction has been established based on the in vitro metabolic stability in the "serum incubation method" using cryopreserved human hepatocytes suspended in 100% human serum. As a novel approach, the inhibitory effect of inhibitors on the metabolism of substrates during...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.23.328

    authors： Shibata Y,Takahashi H,Chiba M,Ishii Y

    更新日期：2008-01-01 00:00:00

  • The influence of aged garlic extract on the uptake of saquinavir and darunavir into HepG2 cells and rat liver slices.

    abstract：:Bioavailability and therapeutic outcome of treatment with HIV-protease inhibitors depends on intestinal and hepatic transporter-enzyme interplay. Liver transport of HIV protease inhibitors (saquinavir, darunavir) was assessed in the presence of aged garlic extract, because the HIV-infected often consume garlic supplem...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.25.307

    authors： Berginc K,Trontelj J,Kristl A

    更新日期：2010-01-01 00:00:00

  • Post-transcriptional regulation of OATP2B1 transporter by a microRNA, miR-24.

    abstract：:Human OATP2B1, a member of organic anion transporting polypeptide family, is expressed in several tissues, including small intestine and liver, and contributes to cellular uptake of endogenous compounds and various drugs. Altered expression of OATP2B1 affects pharmacokinetics of substrate drugs; however, limited infor...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2020.07.007

    authors： Liu W,Nakano M,Nakanishi T,Nakajima M,Tamai I

    更新日期：2020-12-01 00:00:00

  • Numerical analysis of apparent decitabine uptake in HCT116 cells: Incorporation of a bidirectional first-order kinetic parameter for ENT1 transport and Michaelis-Menten parameters for subsequent phosphorylation.

    abstract：:Decitabine (DAC), a DNA methylation inhibitor, is transported into cancer cells mainly via equilibrative nucleoside transporter 1 (ENT1) and subsequently phosphorylated by deoxycytidine kinase (dCK). We previously reported that apparent DAC uptake into cells may be described using a simple compartment model with clear...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2019.10.002

    authors： Ueda K,Nakamura T,Tanaka S,Hosokawa M,Iwakawa S,Ogawara KI

    更新日期：2020-02-01 00:00:00

  • Tissue-specific mRNA expression profiles of human nuclear receptor subfamilies.

    abstract：:Pairs of forward and reverse primers and TaqMan probes specific to each human nuclear receptor were prepared. Analysis of the mRNA expression level of each target of 43 nuclear receptors in total RNA from single and pooled specimens of various human organs (liver, kidney, adrenal gland, lung, heart, brain, cerebellum,...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.19.135

    authors： Nishimura M,Naito S,Yokoi T

    更新日期：2004-04-01 00:00:00

  • Synthesis and evaluation of nevirapine analogs to study the metabolic activation of nevirapine.

    abstract：:Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several ...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2020.01.006

    authors： Tateishi Y,Ohe T,Yasuda D,Takahashi K,Nakamura S,Kazuki Y,Mashino T

    更新日期：2020-04-01 00:00:00

  • 13C-caffeine breath test identifies single nucleotide polymorphisms associated with caffeine metabolism.

    abstract：:We performed a caffeine (N-3-methyl-13C) breath test (CafeBT) to determine whether it can be employed to identify caffeine metabolism-associated single nucleotide polymorphisms. The study included 130 healthy adults (mean age: 21.9 years). Saliva was collected using an Oragene®•DNA saliva collection kit. Breath sample...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2020.03.003

    authors： Ishii M,Ishii Y,Nakayama T,Takahashi Y,Asai S

    更新日期：2020-06-01 00:00:00

  • Relationship between the plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in patients with cancer pain.

    abstract：:This study aimed to evaluate the relationship between the concentrations of plasma fentanyl and serum 4β-hydroxycholesterol based on CYP3A5 genotype and gender in cancer patients. Thirty-three Japanese cancer patients treated with transdermal fentanyl were enrolled. The concentrations of plasma fentanyl and norfentany...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2016.04.001

    authors： Ishida T,Naito T,Sato H,Kawakami J

    更新日期：2016-06-01 00:00:00

  • Genetic polymorphism of bile acid CoA: amino acid N-acyltransferase in Japanese individuals.

    abstract：:In the present study, we identified three novel single nucleotide polymorphisms (SNPs), 147C>T in exon 2 (silent), 602G>C in exon 3 (Arg201Pro), and 1134C>T in exon 4 (silent), in the gene of bile acid CoA: amino acid N-acyltransferase (BAAT) by resequencing the entire coding region and the exon-intron junctions of 10...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.22.125

    authors： Tougou K,Fukuda T,Ito T,Yamazaki H,Fujio Y,Azuma J

    更新日期：2007-04-01 00:00:00

  • Relationship between ABCB1 gene polymorphisms and severe neutropenia in patients with breast cancer treated with doxorubicin/cyclophosphamide chemotherapy.

    abstract：:Chemotherapy-induced neutropenia is one of the major adverse events which results in the reduction of chemotherapy. Doxorubicin is a substrate of the adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) transporter; reportedly, ABCB1 polymorphisms influence doxorubicin pharmacokinetics. We evaluated th...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2014.09.009

    authors： Ikeda M,Tsuji D,Yamamoto K,Kim YI,Daimon T,Iwabe Y,Hatori M,Makuta R,Hayashi H,Inoue K,Nakamichi H,Shiokawa M,Itoh K

    更新日期：2015-04-01 00:00:00

  • Association of ABCC2 genotype with efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer.

    abstract：:This exploratory retrospective study examined the effects of polymorphisms in transporter genes related to irinotecan pharmacokinetics and those in genes related to irinotecan pharmacodynamics on the efficacy of first-line combination chemotherapy with irinotecan, 5-fluorouracil, and folinic acid (leucovorin) (FOLFIRI...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.dmpk-11-rg-128

    authors： Akiyama Y,Fujita K,Ishida H,Sunakawa Y,Yamashita K,Kawara K,Miwa K,Saji S,Sasaki Y

    更新日期：2012-01-01 00:00:00

  • In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs.

    abstract：:Since porphyrins are regarded as endogenous substrates for the ATP-binding cassette (ABC) transporter ABCG2, it is hypothesized that functional impairment owing to genetic polymorphisms or inhibition of ABCG2 by drugs may result in a disruption of cellular porphyrin homeostasis. In the present study, we expressed ABCG...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.22.428

    authors： Tamura A,Onishi Y,An R,Koshiba S,Wakabayashi K,Hoshijima K,Priebe W,Yoshida T,Kometani S,Matsubara T,Mikuriya K,Ishikawa T

    更新日期：2007-12-01 00:00:00

  • Role and relevance of PEPT2 in drug disposition, dynamics, and toxicity.

    abstract：:Pept2 knockout mice are an important tool to evaluate the evolving role and relevance of this proton-coupled oligopeptide transporter beyond drug disposition, where the transporter also modulates the pharmacodynamic and toxicodynamic effects of drug substrates. Our in vivo studies with glycylsarcosine in Pept2 knockou...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章,评审

    doi：10.2133/dmpk.23.236

    authors： Kamal MA,Keep RF,Smith DE

    更新日期：2008-01-01 00:00:00

  • Protein-protein interactions between rat hepatic cytochromes P450 (P450s) and UDP-glucuronosyltransferases (UGTs): evidence for the functionally active UGT in P450-UGT complex.

    abstract：:The interaction between cytochrome P450s (CYP, P450) and UDP-glucuronosyltransferases (UGTs) was studied by co-immunoprecipitation. P450 isoform-selective antibody was used as a probe to co-precipitate UGTs with the P450s from solubilized rat liver microsomes. Antibodies toward CYP3A2, CYP2B2, CYP2C11/13 and CYP1A2 co...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.22.367

    authors： Ishii Y,Iwanaga M,Nishimura Y,Takeda S,Ikushiro S,Nagata K,Yamazoe Y,Mackenzie PI,Yamada H

    更新日期：2007-10-01 00:00:00

  • Effect of protein binding of pilsicainide on the pharmacokinetics.

    abstract：:To evaluate the effect of protein binding of pilsicainide on its clearance and the contribution of protein binding to optimized pilsicainide therapy, clinical laboratory and pharmacokinetic data were studied in 160 Japanese inpatients (Study 1) and 18 Japanese inpatients (Study 2). To determine the relation between pr...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.20.183

    authors： Fukumoto K,Tanemura M,Tsuchishita Y,Kusumoto M,Matsumoto K,Kamakura S,Ueno K

    更新日期：2005-06-01 00:00:00

  • Five novel single nucleotide polymorphisms in the EPHX1 gene encoding microsomal epoxide hydrolase.

    abstract：:Five novel single nucleotide polymorphisms (SNPs) were found in the EPHX1 gene from 96 Japanese epileptic patients. The detected SNPs were as follows: 1) SNP, MPJ6_EX1009; GENE NAME, EPHX1 ACCESSION NUMBER, NT_004525.12; LENGTH, 25 bases; 5'-CCTCACTTCAGTG/ACTGGGCTTTGCC-3'. 2) SNP, MPJ6_EX1013; GENE NAME, EPHX1; ACCESS...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.18.150

    authors： Shiseki K,Itoda M,Saito Y,Nakajima Y,Maekawa K,Kimura H,Goto Y,Saitoh O,Katoh M,Ohnuma T,Kawai M,Sugai K,Ohtsuki T,Suzuki C,Minami N,Ozawa S,Sawada J

    更新日期：2003-01-01 00:00:00

  • Effect of nuclear receptor downregulation on hepatic expression of cytochrome P450 and transporters in chronic hepatitis C in association with fibrosis development.

    abstract：:Analysis of mRNAs from liver biopsy samples of patients with chronic hepatitis C revealed that the levels of nuclear receptor expression were correlated with those of drug-metabolizing enzymes and transporters in relation to the development of fibrosis. Overall, the median mRNA level was largely dependent on fibrosis ...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.dmpk-11-rg-077

    authors： Hanada K,Nakai K,Tanaka H,Suzuki F,Kumada H,Ohno Y,Ozawa S,Ogata H

    更新日期：2012-01-01 00:00:00

  • Physiologically-based modeling of monoclonal antibody pharmacokinetics in drug discovery and development.

    abstract：:Over the past few decades, monoclonal antibodies (mAbs) have become one of the most important and fastest growing classes of therapeutic molecules, with applications in a wide variety of disease areas. As such, understanding of the determinants of mAb pharmacokinetic (PK) processes (absorption, distribution, metabolis...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章,评审

    doi：10.1016/j.dmpk.2018.11.002

    authors： Glassman PM,Balthasar JP

    更新日期：2019-02-01 00:00:00

  • Changes in CYP1A2 activity in humans after 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) administration using caffeine as a probe drug.

    abstract：:3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 i...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.dmpk-12-rg-032

    authors： Yubero-Lahoz S,Pardo R,Farre M,Mathuna BÓ,Torrens M,Mustata C,Perez-Mañá C,Langohr K,Carbó ML,de la Torre R

    更新日期：2012-01-01 00:00:00

  • Emerging new technology: QSAR analysis and MO Calculation to characterize interactions of protein kinase inhibitors with the human ABC transporter, ABCG2 (BCRP).

    abstract：:Protein kinases are potential drug targets for the treatment of a variety of diseases, including cancer. In particular, specific tyrosine kinase inhibitors are rapidly being developed as new drugs for the inhibition of malignant cell growth and metastasis formation. Most of these newly developed tyrosine kinase inhibi...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章,评审

    doi：10.2133/dmpk.25.72

    authors： Saito H,An R,Hirano H,Ishikawa T

    更新日期：2010-01-01 00:00:00

  • New SRM data dependent exclusion (MS)n measurement for structural determination of drug metabolites using LC/ESI/Ion trap MS.

    abstract：:New SRM (selected reaction monitoring) data dependent exclusion (MS)(n) measurement makes it possible to obtain MS(3) fragmentation data for all MS(2) fragments, useful for structural determination of drug metabolites using ESI ion trap. MS(2) fragments are produced by cleavage of all protonated molecules at the lone ...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.2133/dmpk.18.390

    authors： Tozuka Z,Kaneko H,Shiraga T,Beppu M,Niwa T,Kawamura A,Kagayama A

    更新日期：2003-01-01 00:00:00

  • The population genetics of pharmacogenomics VIP variants in the Sherpa population.

    abstract：:Polymorphic distributions of pharmacogenes among some ethnicities are under-represented in current pharmacogenetic research. Particularly, there is a paucity of pharmacogenetic information in the Sherpa population in Tibet. We used the Sequenom MassARRAY single nucleotide polymorphism (SNP) genotyping technology to de...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2015.11.007

    authors： Wang L,Ren Y,Shi X,Yuan D,Liu K,Geng T,Li G,Kang L,Jin TB

    更新日期：2016-02-01 00:00:00

  • Detection of CYP2D6 polymorphism using Luminex xTAG technology in autism spectrum disorder: CYP2D6 activity score and its association with risperidone levels.

    abstract：:CYP2D6 is involved in the biotransformation of a large number of drugs, including risperidone. This study was designed to detect CYP2D6 polymorphisms with a Luminex assay, including assessment the relationship of CYP2D6 polymorphisms and risperidone plasma concentration in autism spectrum disorder children (ASD) treat...

    journal_title：Drug metabolism and pharmacokinetics

    pub_type： 杂志文章

    doi：10.1016/j.dmpk.2016.01.005

    authors： Vanwong N,Ngamsamut N,Hongkaew Y,Nuntamool N,Puangpetch A,Chamnanphon M,Sinrachatanant A,Limsila P,Sukasem C

    更新日期：2016-04-01 00:00:00