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Luch, A.* ; Schober, W.* ; Soballa, V.J.* ; Raab, G.* ; Greim, H. ; Jacob, J.* ; Doehmer, J.* ; Seidel, A.*

Metabolic activation of dibenzo[a,l]pyrene by human cytochrome P450 1A1 and P450 1B1 expressed in V79 Chinese hamster cells.

Chem. Res. Toxicol. 12, 353-364 (1999)
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Metabolic activation of the strongly carcinogenic polycyclic aromatic hydrocarbon (PAH) dibenzo[a,l]pyrene (DB[a,l]P) and its trans-8,9-dihydrodiol (trans-8,9-diol) catalyzed by human cytochromes P450 (P450) 1A1 and 1B1 was investigated. DNA binding of DB[a,l]P in mammalian cell lines has previously been shown to be preferentially mediated by fjord region DB[a,l]P-11,12-dihydrodiol 13,14-epoxides (DB[a,l]PDE). In order to elucidate different capabilities of both P450 enzymes for metabolic activation of DB[a, l]P V79 Chinese hamster cells, stably expressing human P450s 1A1 or 1B1 have been exposed to the parent PAH or its racemic trans-8, 9-diol. For this purpose, synthesis and spectroscopic characterization of the trans-DB[a,l]P-8,9-diol and its individual enantiomers have been achieved. Both human P450-expressing cell lines were capable of transforming DB[a,l]P to its fjord region DB[a, l]PDE, but the extent of metabolism to DB[a,l]PDE catalyzed by human P450 1B1 was higher compared to human P450 1A1 at all times measured. On the other hand, cytotoxicity studies performed with the same incubation systems emerged stronger effects by DB[a,l]P and its enantiomeric trans-11,12-diols in human P450 1A1-expressing cells. Both human P450 enzymes stereospecifically catalyzed the formation of the (-)-DB[a,l]P-11,12-diol with R,R-configuration, whereas only the human P450 1A1-expressing cells form small amounts of the K-region trans-8,9-diol with high excess of the (+)-(8R, 9R)-enantiomer. Application of trans-DB[a,l]P-8,9-diol in metabolism studies revealed that this compound is converted by human P450s 1A1 and 1B1 to several diol phenols and bis-diols. However, and even at concentrations as high as 10 microM, in both cell lines the trans-DB[a,l]P-8,9-diol showed no cytotoxicity at all, suggesting that an activation of DB[a,l]P via further oxidation of the K-region trans-8,9-diol plays a minor role.
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Publication type Article: Journal article
Document type Scientific Article
Keywords POLYCYCLIC AROMATIC-HYDROCARBONS; REGION 11,12-DIOL 13,14-EPOXIDES; TUMOR-INITIATING ACTIVITY; ENVIRONMENTAL CARCINOGEN DIBENZOPYRENE; DNA ADDUCT FORMATION; RAT MAMMARY-GLAND; MOUSE SKIN; K-REGION; ABSOLUTE-CONFIGURATION; TRANS-DIHYDRODIOLS
ISSN (print) / ISBN 0893-228X
e-ISSN 1520-5010
Quellenangaben Volume: 12, Issue: 4, Pages: 353-364 Article Number: , Supplement: ,
Publisher American Chemical Society (ACS)
Reviewing status Peer reviewed