کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5846293 | 1128474 | 2014 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Hepatocyte-based in vitro model for assessment of drug-induced cholestasis
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کلمات کلیدی
HBSSGDCASandwich-cultured hepatocytesSCRHSandwich-cultured rat hepatocytesGCDCANOAELBSEP/BsepALTPBSFBSTCABAs - BASDMSO - DMSOAspartate aminotransferase - آسپارتات ترانس آمیناز یا AST Alanine aminotransferase - آلانین آمینوترانسفرازALP - آلکالن فسفاتازSCH - اس اسTaurocholic acid - اسید تاورچولیکCholic acid - اسید چلیکGlycodeoxycholic acid - اسید گلیکودوکسو هیکولGlycochenodeoxycholic acid - اسید گلیکوزید سدیم اسیدBile acids - اسیدهای صفراویDICI - بگوDimethyl sulfoxide - دیمتیل سولفواکسیدfetal bovine serum - سرم جنین گاوPhosphate buffered saline - فسفات بافر شورHanks' balanced salt solution - محلول نمک متعادل هانکسNo observed adverse effect level - هیچ عوارض جانبی مشاهده نشده
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24-48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI â¤Â 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI â¤Â 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 274, Issue 1, 1 January 2014, Pages 124-136
Journal: Toxicology and Applied Pharmacology - Volume 274, Issue 1, 1 January 2014, Pages 124-136
نویسندگان
Sagnik Chatterjee, Lysiane Richert, Patrick Augustijns, Pieter Annaert,