0000000000405005
AUTHOR
Jürgen Jacob
Metabolic activation of dibenzo[a,l]pyrene by human cytochrome P450 1A1 and P450 1B1 expressed in V79 Chinese hamster cells.
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…
Metabolism of Phenanthrene, Benz[a]anthracene, Benzo[a]pyrene, Chrysene and Benzo[c]phenanthrene by Eight cDNA-expressed Human and Rat Cytochromes P450
Abstract Phenanthrene, benz[a]anthracene, chrysene, benzo[c]phenanthrene, and benzo[a]pyrene have been studied for their regiospecific oxidation by five human (1A1, 1A2, 2A6, 2E1, 3A4) and three rat (1A1, 1A2, 2B1) CYP isoforms. All substrates are preferentially metabolized by CYP1A1 and CYP1A2 in human and rat. Other isoforms play a minor role if at all. Significant differences between human and rat CYP isoforms can be recognized with regard to the regiospecific oxidation of PAH. For instance, K-region oxidation is more pronounced in rat than in human CYP1A1 and CYP1A2. Hence, extrapolation from metabolism studies in rodents to human may be limited.
Regio- and stereoselectivity in the metabolism of benzo[c]phenanthrene mediated by genetically engineered V79 Chinese hamster cells expressing rat and human cytochromes P450.
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,…