کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5862863 1133784 2013 8 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Effect of combining in vitro estrogenicity data with kinetic characteristics of estrogenic compounds on the in vivo predictive value
چکیده انگلیسی

With the ultimate aim of increasing the utility of in vitro assays for toxicological risk assessment, a method was developed to calculate in vivo estrogenic potencies from in vitro estrogenic potencies of compounds by taking into account systemic availability. In vitro estrogenic potencies of three model compounds (bisphenol A, genistein, and 4-nonylphenol) relative to ethinylestradiol (EE2), determined with the estrogen receptor alpha (ERα) transcriptional activation assay using hER-HeLa-9903 cells, were taken from literature and used to calculate the EE2 equivalent (EE2EQ) effect doses in the predominantly ERα-dependent rat uterotrophic assay. Compound-specific differences in hepatic clearance relative to the reference compound EE2 were determined in vitro to examine whether in vivo estrogenic potencies reported in literature could be more accurately estimated. The EE2EQ doses allowed to predict in vivo uterotrophic responses within a factor of 6-25 and the inclusion of the hepatic clearance further improved the prediction with a factor 1.6-2.1 for especially genistein and bisphenol A. Yet, the model compounds still were less potent in vivo than predicted based on their EE2 equivalent estrogenic potency and hepatic clearance. For further improvement of the in vitro to in vivo predictive value of in vitro assays, the relevance of other kinetic characteristics should be studied, including binding to carrier proteins, oral bioavailability and the formation of estrogenic metabolites.

► Values for in vitro estrogenicity were combined with in vitro determined hepatic clearance values. ► This was performed for the compounds ethinylestradiol, bisphenol A, genistein and nonylphenol. ► The outcome was compared with reported in vivo estrogenic effects in the rat uterotrophic assay. ► Correction for compound-specific differences in hepatic clearance more accurately estimated in vivo estrogenic potencies.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology in Vitro - Volume 27, Issue 1, February 2013, Pages 44-51
نویسندگان
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