| Abstrakt: |
Regio- and stereoselective metabolism mediated by cytochrome P450 (CYP) and metabolite-dependent cytotoxicity of benzo[c]phenanthrene (B[c]Ph) and its trans-3,4-dihydrodiol, the metabolic precursor of the carcinogenic fjord-region B[c]Ph-3,4-dihydrodiol 1,2-epoxides (B[c]PhDE), were investigated with V79 Chinese hamster cells genetically engineered for three rat and six human CYP isoforms. The order of the capabilities of the CYP isoforms to metabolize B[c]Ph was as follows: h1A1 > r1A1 > r1A2 > h1B1 > h1A2 > r2B1 > > h2E1 > h2A6 > h3A4. Regardless of the species, all individual CYP isoforms preferentially catalyzed the oxidation of B[c]Ph at the 5,6-position (K-region) except human CYP1A1 and human CYP1A2, which oxidized both the 5,6- and the 3,4-position with similar efficiency. While human CYP1A1, rat CY1A1 and rat CYP1A2 formed almost exclusively the (-)-B[c]Ph-3R,4R-dihydrodiol,human CYP1A2 produced both the (-)-3R,4R- and the (+)-3S,4S-dihydrodiol enantiomers in a ratio of 2:1. Stereoselective activation of B[c]Ph, the (q )-B[c]Ph-3,4-dihydrodiol and its ( - )-3R,4R-enantiomer tothe fjord-region (-)-anti-B[c]PhDE occurred upon incubation with ratCYP1A1 and rat CYP1A2 as indicated by the formation of two stereoisomeric tetraols, the hydrolysis products of the labile anti-B[c]PhDE. The formation of tetraols in the culture mediurn was accompanied by aconcentration-dependent increase in cytotoxicity indicating that this effect was mediated by the fjord-region (-)-anti-B[c]PhDE formed asreactive intermediate. All human and rat CYP-expressing V79 cell lines investigated did not show any significant capacity to metabolize the (+)-3S,4S-dihydrodiol. The present study indicates that the human CYP isoforms 1A1 and 1B1 have complementary catalytic properties to activate B[c]Ph to its fjord-region B[c]PhDE, whereas other human isoforms, play a minor role. Activation of B[c]Ph by human CYP1Al and 1B1is less efficient than by rat CYP1A1 or rat CYP1A2, but proceeds with simi [ABSTRACT FROM AUTHOR] |
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