کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5859205 | 1562333 | 2014 | 9 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Interindividual variation in response to xenobiotic exposure established in precision-cut human liver slices
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کلمات کلیدی
LMPNAD(P)H dehydrogenase, quinone 1BNAglutathione S-transferase mu 1CDKN1ABPDEPHHcopy DNANQO1N-acetyl-p-benzoquinone imineNAPQIAPAPBMDBAPRT-PCRAFBCyPAHRNaOHHEPES2-nitrofluorene - 2-نیتروفلوئورن4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acidcDNA - cDNADMSO - DMSOprimary human hepatocytes - hepatocytes اولیه انسانSmall interfering RNA - RNA تداخل کوچکsiRNA - siRNAAflatoxin B1 - آفلاتوکسین B1EDTA - اتیلن دی آمین تترا استیک اسید Ethylenediaminetetraacetic acid - اتیلینیدامین تتراستیک اسیدAcetaminophen - استامینوفن Critical Effect Size - اندازه اثر بحرانیCES - اینPrecision-cut liver slices - برش کبد دقیقGene expression - بیان ژنBayesian network analysis - تجزیه و تحلیل شبکه بیزیinterindividual variation - تنوع بین فردیbenchmark dose - دوز معادلDimethyl sulfoxide - دیمتیل سولفواکسیدSodium hydroxide, Caustic Soda - سدیم هیدروکسید، کاستیک سودا، سود سوزآورCarcinogens - سرطان زاCytochrome P450 - سیتوکروم پی۴۵۰Bayesian network - شبکه بیزی، شبکه بیزینEnzyme activity - فعالیت آنزیمlactate dehydrogenase - لاکتات دهیدروژناز LDH - لاکتات دهیدروژناز به صورت مختصر شده LDH cyclin-dependent kinase inhibitor 1A - مهار کننده 1A کیناز وابسته به کینازlow melting point - نقطه ذوب پایینreverse transcription polymerase chain reaction - واکنش زنجیره ای پلیمراز رونویسی معکوسaryl hydrocarbon receptor - گیرنده آرویل هیدروکربن
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Large differences in toxicity responses occur within the human population. In this study we evaluate whether interindividual variation in baseline enzyme activity (EA)/gene expression (GE) levels in liver predispose for the variation in toxicity responses by assessing dose-response relationships for several prototypical hepatotoxicants. Baseline levels of cytochrome-P450 (CYP) GE/EA were measured in precision-cut human liver slices. Slices (n = 4-5/compound) were exposed to a dose-range of acetaminophen, aflatoxin B1, benzo(α) pyrene or 2-nitrofluorene. Interindividual variation in induced genotoxicity (COMET-assay and CDKN1A/p21 GE) and cytotoxicity (lactate dehydrogenase-leakage), combined with NQO1- and GSTM1-induced GE-responses for oxidative stress and GE-responses of several CYPs was evaluated. The benchmark dose-approach was applied as a tool to model exposure responses on an individual level. Variation in baseline CYP levels, both GE and EA, can explain variation in compound exposure-responses on an individual level. Network analyses enable the definition of key parameters influencing interindividual variation after compound exposure. For 2-nitrofluorene, this analysis suggests involvement of CYP1B1 in the metabolism of this compound, which represents a novel finding. In this study, GSTM1 which is known to be highly polymorphic within the human population, but so far could not be linked to toxicity in acetaminophen-poisoned patients, is suggested to cause interindividual variability in acetaminophen-metabolism, dependent on the individual's gene expression-responses of CYP-enzymes. This study demonstrates that using interindividual variation within network modelling provides a source for the definition of essential and even new parameters involved in compound-related metabolism. This information might enable ways to make more quantitative estimates of human risks.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology - Volume 323, 2 September 2014, Pages 61-69
Journal: Toxicology - Volume 323, 2 September 2014, Pages 61-69
نویسندگان
Marlon J.A. Jetten, Sandra M. Claessen, Cornelis H.C. Dejong, Agustin Lahoz, José V. Castell, Joost H.M. van Delft, Jos C.S. Kleinjans,