Abstract:
:We report here a comprehensive evaluation of the effects of culture duration on the gene expression of P450 isoforms, uptake transporters and efflux transporters in human hepatocyte cultured in the absence and presence of the prototypical proinflammatory cytokine, interleukin-6 (IL-6). Primary collagen-matrigel sandwich cultures of human hepatocytes were cultured in supplemented William's E medium containing 0, 0.1, 0.5 and 5 ng/mL of IL-6 for the time periods of 2, 6, 12, 24 and 48 hrs. Real-time PCR was performed to quantify gene expression of acute phase proteins (suppressor of cytokine signaling 3 (SOCS-3), c-reactive protein (CRP) and lipopolysaccharide (LPS)-binding proteins (LBP)); P450 isoforms (CYPs 1A2, 2B6, 2C8, 2C9, 2D6, 3A4, and 3A5), uptake transporters (SLC10A1, SLC22A1, SLC22A7, SLCO1B1, SLCO1B3, SLCO2B1) and efflux transporters (ABCB1, ABCB11, ABCC2, ABCC3, ABCC4, ABCG2). SOCS-3, CRP, and LBP were extensively induced by IL-6, with maximal induction observed at 2 (SOCS-3) and 12 hrs (CRP; LBP), demonstrating that the cultured human hepatocytes responded to IL-6 treatment. In the untreated group (control), gene expression of P450 isoforms and uptake transporters decreased while efflux transporters remained relatively stable or increased with cultured duration. IL-6 predominantly caused down regulations of the genes studied, with the most significant changes observed at different treatment durations, apparently related to the stability of the basal levels of gene expression. For instance, for genes with unstable expression, which would decrease rapidly in culture (e.g CYP3A4), the most definitive down regulatory effects were observed at a relatively early time point (e.g. 12 hrs). In contrast, a longer treatment duration (e.g. 48 hrs) was required for genes with relatively stable expression levels in culture (e.g. ABCB1). Based on our findings, evaluation of multiple treatment durations rather than single treatment duration is recommended for the evaluation of biotherapeutics in cultured human hepatocytes where down regulation is expected.
journal_name
Curr Drug Metabjournal_title
Current drug metabolismauthors
Yang Q,Doshi U,Li N,Li APdoi
10.2174/138920012802138570subject
Has Abstractpub_date
2012-09-01 00:00:00pages
938-46issue
7eissn
1389-2002issn
1875-5453pii
CDM-EPUB-20120328-011journal_volume
13pub_type
杂志文章abstract:BACKGROUND:The red-crowned crane (Grus japonensis) is one of the most vulnerable bird species in the world. Mycotoxins are toxic secondary metabolites produced by fungi and considered naturally unavoidable contaminants in animal feed. Our recent survey indicated that the mycotoxins had the potential to contaminate redc...
journal_title:Current drug metabolism
pub_type: 杂志文章
doi:10.2174/1389200221666200726221126
更新日期:2020-01-01 00:00:00
abstract::This review provides an overview of the in vitro methods currently used in studies of intestinal drug metabolism and active efflux with a special emphasis on the efflux- metabolism interplay. These methods include e.g. expressed enzymes or efflux transporters, fractionated intestinal cells, cell lines, primary cells, ...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:
更新日期:2013-01-01 00:00:00
abstract::Graphene possesses a wide range of potential biomedical applications because of the unique physical and chemical properties. However, the side effects of grapheme and its derivatives on a number of biological models even on human body are still not very clear. Therefore, to properly assess the potential risk of graphe...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/138920021131400108
更新日期:2013-10-01 00:00:00
abstract:BACKGROUND:The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin tra...
journal_title:Current drug metabolism
pub_type: 杂志文章
doi:10.2174/1389200221666200620201348
更新日期:2020-01-01 00:00:00
abstract::Arachidonic acid (AA) is metabolized by enzymes of the cytochrome P450 (CYP) 4A and CYP4F subfamilies to 20- hydroxyeicosatetraeonic acid (20-HETE), which plays an important role in the cardiovascular system. In the current work, we reviewed the formation of 20-HETE in different species by different CYPs; 20-HETE meta...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200211314060007
更新日期:2013-07-01 00:00:00
abstract::The occurrence of idiosyncratic adverse drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use and even in its withdrawal. Metabolic activation of relatively inert functional groups to reactive electrophilic intermediates is considered to be an obligato...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200054021799
更新日期:2005-06-01 00:00:00
abstract::To understand the sophisticated dynamic behaviors of drug elution and permeation in the gastrointestinal tract (GIT), researchers have tried to reemerge it by employing various in vitro experimental models. However, official in vitro apparatuses routinely used for quality control purposes, employ simple, non-physiolog...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200216666150812123836
更新日期:2015-01-01 00:00:00
abstract::Part I of this article published in the previous issue of Current Drug Metabolism discussed the substrate specificity, inhibitor selectivity and structure-activity relationship (SAR) of human CYP2C9. The features of CYP2C9 pharmacophore and SAR models have been elaborated. Part II of this article will address the homo...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/138920009790820101
更新日期:2009-12-01 00:00:00
abstract::The biochemical activities of plant flavonoids and stilbenoids point to many health-related applications, hampered however by a low bioavailability associated with rapid metabolic modification. A possible approach to overcome this obstacle is the development of prodrugs. In this review we provide some background infor...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200214666131211160005
更新日期:2014-01-01 00:00:00
abstract:BACKGROUND:Clinical studies during pregnancy are rare due to ethical and practical limitations. Giving pregnant females the same dosing regimen used in adult males or nonpregnant females is inappropriate. Pregnancy physiologically-based pharmacokinetic modeling is a powerful tool that can be used to refine pharmacother...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200219666180702104034
更新日期:2018-01-01 00:00:00
abstract::Photodynamic therapy (PDT) combines photosensitizer, visible light and oxygen, which has the characteristics of high selectivity, minimal invasiveness, low side effect, and allowing repetitive application. The photophysics and mechanisms leading to cell death mediated by PDT have been studied extensively, and PDT has ...
journal_title:Current drug metabolism
pub_type: 杂志文章
doi:10.2174/138920009790274559
更新日期:2009-10-01 00:00:00
abstract::Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Cl...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/138920007780655469
更新日期:2007-05-01 00:00:00
abstract::One of the major advances in the recent history of the treatment of HIV infections has been the development of different classes of effective antiretroviral drugs. In particular, the reverse transcriptase (RT) inhibitors still represent the majority of the clinically used anti-HIV drugs and constitute the main backbon...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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abstract:BACKGROUND:Nanoparticles (NPs) are being used extensively owing to their increased surface area, targeted delivery and enhanced retention. NPs have the potential to be used in many disease conditions. Despite widespread use, their toxicity and clinical safety still remain a major concern. OBJECTIVE:The purpose of this...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200221666200103091753
更新日期:2019-01-01 00:00:00
abstract::There are several clinically useful endoperoxides, mainly artemisinin derivatives available in market for the treatment of malaria. These are highly potent drugs, with fastest parasite reduction ratio, broadest parasite stage specificity and effectiveness against all species of plasmodium in human. Endoperoxides are c...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/138920009787846323
更新日期:2009-03-01 00:00:00
abstract::The pharmacological effects of a drug are highly dependent on the absorption, metabolism, elimination, and distribution of the drug. In the past few years it has become apparent that transport proteins play a major role in regulating the distribution, elimination and metabolism of some drugs. As a consequence of our n...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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更新日期:2002-06-01 00:00:00
abstract::Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important for safety and efficacy considerations. Early identification of transporters involved gu...
journal_title:Current drug metabolism
pub_type: 杂志文章
doi:10.2174/1389200221999210101233340
更新日期:2021-01-01 00:00:00
abstract:BACKGROUND:Neuropsychiatric diseases primarily characterized by dementia stand third in the global list of diseases causing disability. The poor water solubility, erratic oral absorption, low bioavailability, poor intestinal absorption, and the impeding action of the blood-brain barrier (BBB) are the major factors limi...
journal_title:Current drug metabolism
pub_type: 杂志文章
doi:10.2174/1573399816666200627214129
更新日期:2020-01-01 00:00:00
abstract::In vitro models of the liver using isolated primary hepatocytes have been used as screens for measuring the metabolism, toxicity and efficacy of xenobiotics, for studying hepatocyte proliferation, and as bioartificial liver support systems. Yet, primary isolated hepatocytes rapidly lose liver specific functions when m...
journal_title:Current drug metabolism
pub_type: 杂志文章
doi:10.2174/138920005774832632
更新日期:2005-12-01 00:00:00
abstract::Knowledge regarding cytochrome P450 (P450) is crucial to the fields of drug therapy and drug development, as well as in our understanding of the mechanisms underlying the metabolic activation of potentially toxic and carcinogenic compounds. Escherichia coli is the most extensively utilized host in the production of re...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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更新日期:2006-05-01 00:00:00
abstract::Thiopurines such as azathioprine, 6-mercaptopurine and 6-thioguanine are antimetabolites that have been used for several decades in the treatment of several diseases including inflammatory bowel diseases. Additional anti-inflammatory properties of these thiopurines have been discovered in recent years. Thiopurine meta...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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更新日期:2009-11-01 00:00:00
abstract::Several epidemiological studies throughout the years have suggested that polyphenols from fruits and vegetables promote health and reduce the risk of certain chronic and neurodegenerative diseases. Yet, it has been proved to be extremely difficult to quantitatively establish the benefit afforded by polyphenols, princi...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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更新日期:2014-01-01 00:00:00
abstract::In recent years several arylpiperazine derivatives have reached the stage of clinical application, mainly for the treatment of depression, psychosis or anxiety. Examples are the pyrimidinylpiperazine buspirone, the chlorophenylpiperazine derivatives nefazodone and trazodone, the dichlorophenylpiperazine aripiprazole a...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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更新日期:2007-08-01 00:00:00
abstract::It has long been suggested that some of the neuropharmacological, neurochemical and behavioural effects of ethanol are mediated by its first metabolite, acetaldehyde. In spite of the well documented psychoactivity of acetaldehyde, the precise role of this compound in alcohol abuse remains a matter of intense debate am...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/138920007782109797
更新日期:2007-10-01 00:00:00
abstract::This paper reviews the empirical methods of quantitative microdialysis that have been used to interpret the results obtained from pharmacokinetic studies. The concept of extraction efficiency or recovery and the properties of recovery in vivo (variation with flow rate, time dependency and influence of the mode of admi...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
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更新日期:2005-04-01 00:00:00
abstract::Maternal antenatal therapy with glucocorticoids (GC) is routinely used to prevent lung immaturity. The potential harmful effects on other organs, including in particular the central nervous system (CNS), are still controversial. In the present review we aimed to investigate: i) the beneficial and detrimental effects o...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:
更新日期:2013-02-01 00:00:00
abstract:BACKGROUND:Drug-induced cholestasis is a risk factor in the progression of drug candidates, and poses a serious health hazard if not detected before going into a human. Intrahepatic accumulation of Bile Acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis. METHODS:This review wil...
journal_title:Current drug metabolism
pub_type: 杂志文章,评审
doi:10.2174/1389200219666180427165035
更新日期:2018-01-01 00:00:00
abstract::The aim of the present study was to develop and improve methods for phenotyping of CYP2E1, an important enzyme in the biotransformation of many industrial chemicals, therapeutic drugs and endogenous substances. The possibility to measure CYP2E1 activity in lymphocytes by using p-nitrophenol as a substrate and CYP2E1 p...
journal_title:Current drug metabolism
pub_type: 临床试验,杂志文章
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更新日期:2007-06-01 00:00:00
abstract::Brain, the centre of the nervous system and an integral part the body, is protected by two anatomical and physiological barriers- Blood-Brain Barrier (BBB) and Blood-Cerebrospinal Fluid Barrier (BCSFB). Blood-Brain Barrier is a very complex and highly organized multicellular structure that shields the brain from harmf...
journal_title:Current drug metabolism
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更新日期:2017-01-01 00:00:00
abstract:BACKGROUND:Bioequivalence studies are a vital part of drug development. The average bioequivalence approach is the standard method of assessment to conclude whether the generic product is bioequivalent to the innovator product. Of late, debates are on whether the average bioequivalence approach adequately addresses dru...
journal_title:Current drug metabolism
pub_type: 杂志文章,随机对照试验
doi:10.2174/1389200221666200401105119
更新日期:2020-01-01 00:00:00