The use of transgenic cell lines for evaluating toxic metabolites of carbamazepine
| Autor: | Valentine Jl, Julian E.A. Leakey, John E. Seng, Valentine Cr, Casciano D |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Health
Toxicology and Mutagenesis Metabolite Biology Pharmacology Toxicology Gas Chromatography-Mass Spectrometry Mixed Function Oxygenases Cytochrome P-450 CYP2A6 chemistry.chemical_compound Oxygen Consumption Cytochrome P-450 Enzyme System Cytochrome P-450 CYP1A2 Microsomes Cytochrome P-450 CYP1A1 Tumor Cells Cultured Cytochrome P-450 CYP3A Humans Transgenes Cytotoxicity Chromatography High Pressure Liquid Lymphoblast Cytochrome P450 Cytochrome P-450 CYP2E1 Cell Biology Metabolism Carbamazepine chemistry Biochemistry Cell culture Toxicity biology.protein Microsome Aryl Hydrocarbon Hydroxylases |
| Zdroj: | Cell Biology and Toxicology. 12:155-165 |
| ISSN: | 1573-6822 0742-2091 |
| Popis: | Human lymphoblastoid cell lines transgenic for human CYP450s were evaluated for the identification of toxic metabolites of the anticonvulsant drug carbamazepine (CBZ). Human CYP450 isoforms expressed by these cell lines included 1A1, 1A2, 2E1, 2A6, and 3A4. A dose-dependent inhibition of population growth from 50-200 micrograms/ml CBZ was detected by measuring cell number and respiration. The inhibition increased with the growth rate of the various lines, which correlated inversely with the presence of CYP450s, and may have been caused by CBZ itself. Cytotoxicity was observed only at the highest dose and in the line lacking transfected CYP450s. Microsomal preparations from hCYP3A4/OR cells converted CBZ into its principal oxidative metabolite, carbamazepine-10,11-epoxide (CBZ-E), at a rate of 630 pmol/min per mg protein, confirming a major role of CYP3A4 in this reaction. However, no CBZ-E (or any metabolite) was recovered from any whole-cell incubation even though hCYP3A4 cells readily converted testosterone to 6 beta-hydroxytestosterone. This suggests that differences exist between whole-cell and microsomal preparations of lymphoblastoid cells in their ability to metabolize CBZ. |
| Databáze: | OpenAIRE |
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