کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2581930 1130213 2007 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Structure–activity relationships for halobenzene induced cytotoxicity in rat and human hepatoctyes
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
Structure–activity relationships for halobenzene induced cytotoxicity in rat and human hepatoctyes
چکیده انگلیسی

Halobenzenes are ubiquitous environmental contaminants, which are hepatotoxic in both rodents and humans. The molecular mechanism of halobenzene hepatotoxicity was investigated using Quantitative structure–activity relationships (QSAR) and accelerated cytotoxicity mechanism screening (ACMS) techniques in rat and human hepatocytes. The usefulness of isolated hepatocytes for prediciting in vivo xenobiotic toxicity was reassessed by correlating the LC50 of 12 halobenzene congeners in phenobarbital (PB) induced rat hepatocytes in vitro determined by ACMS to the hepatotoxicities reported in vivo in PB-induced male Sprague–Dawely (SD) rats. A high correlation (r2 = 0.90) confirmed the application of hepatocytes as a “gold standard” for toxicity testing in vitro. QSARs were derived to determine the physico-chemcial variables that govern halobenzene toxicity in PB-induced rat, normal rat and human hepatocytes. We found that toxicity in normal rat and normal human hepatocytes both strongly correlate with hydrophobicity (log P), ease of oxidation (EHOMO, energy of the highest molecular orbital) and on the asymmetric charge distribution according to arrangement of halogen substituents (dipole moment, μ). This suggests that halobenzene interaction with cytochrome P450 for oxidation is the metabolic activating path for toxicity and is similar in both species. In PB-induced rat hepatocytes the QSAR derivation is changed, where halobenzene toxicity strongly correlates to log P and dipole moment, but not EHOMO. The changed QSAR suggests that oxidation is no longer the rate-limiting step in the cytotoxic mechanism when CYP2B/3A levels are increased, confirming CYP450 oxidation as the metabolic activating step under normal conditions.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemico-Biological Interactions - Volume 165, Issue 3, 20 February 2007, Pages 165–174
نویسندگان
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