Differential Protection by Rat UDP-Glucuronosyltransferase 1A7 against Benzo[a]pyrene-3,6-quinone- versus Benzo[a]pyrene-Induced Cytotoxic Effects in Human Lymphoblastoid Cells
| Autor: | Fay K. Kessler, Andrew D. Grove, Llewellyn Gc, Joseph K. Ritter, Crespi Cl, Kimber L. White |
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| Rok vydání: | 2000 |
| Předmět: |
Herpesvirus 4
Human Cell Survival Blotting Western Genetic Vectors Apoptosis Biology Transfection Toxicology Cell Line chemistry.chemical_compound Glucuronides Benzo(a)pyrene Animals Humans Drug Interactions Lymphocytes Benzopyrenes Glucuronosyltransferase Cytotoxicity Epoxide hydrolase Chromatography High Pressure Liquid Carcinogen Epoxide Hydrolases Pharmacology Cell growth Flow Cytometry Rats Biochemistry chemistry Cell culture Microsomal epoxide hydrolase Growth inhibition Cell Division |
| Zdroj: | Toxicology and Applied Pharmacology. 162:34-43 |
| ISSN: | 0041-008X |
| DOI: | 10.1006/taap.1999.8815 |
| Popis: | UDP-glucuronosyltransferase 1A7 (UGT1A7) is a polyaromatic hydrocarbon (PAH)-inducible UGT with activity toward various benzo[a]pyrene (B[a]P) metabolites. To investigate the influence of rat UGT1A7 on B[a]P-induced cytotoxicity, human lymphoblastoid L3 cells were transfected with pMF6 (control expression vector), p167Dtk2 (microsomal epoxide hydrolase expression vector), or p167Dtk2-1A7 (epoxide hydrolase/UGT1A7 coexpression vector), and the cell populations were compared for sensitivity to B[a]P-induced effects. B[a]P inhibited cell proliferation and decreased relative cell survival of p167Dtk2 and p167Dtk2-1A7 cells to a similar extent. Metabolism studies using [(3)H]B[a]P revealed increased formation of glucuronide conjugates of B[a]P-4,5-diol, 3-OH-, or 9-OH-B[a]P and an unidentified metabolite by p167Dtk2-1A7 cells, but the presence of unconjugated metabolites suggested that glucuronidation capacity may be limited. No differences between p167Dtk2 and p167Dtk2-1A7 L3 cells were observed in the growth inhibitory effects of 3-OH-B[a]P or B[a]P-7,8-diol, but p167Dtk2-1A7-expressing cells were found to be less sensitive to B[a]P-3,6-quinone-induced effects on cell proliferation and relative cell survival. The effect was also observed in AHH-1 lymphoblastoid cells expressing UGT1A7 without epoxide hydrolase. The UGT1A7-expressing AHH-1 cells were also less sensitive to growth inhibition by B[a]P-1,6-quinone and B[a]P-6,12-quinone. Flow cytometric analysis of vehicle and B[a]P-3, 6-quinone-exposed cell populations showed an association between UGT1A7 expression and resistance to B[a]P-3,6-quinone-induced apoptosis and loss of cell viability. These data suggest that UGT1A7 may be preferentially active toward B[a]P-quinones and that UGT1A7 may represent the PAH-inducible UGT activity previously implicated in protection against toxic redox cycling by B[a]P-3,6-quinone. |
| Databáze: | OpenAIRE |
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