Metabolic activation of the potent carcinogen dibenzo[a,l]pyrene by human recombinant cytochromes P450, lung and liver microsomes

Abstract

The metabolic activation of dibenzo[a,l]pyrene (DB[a,l]P), recently considered the most potent carcinogen among all polycyclic aromatic hydrocarbons, to the 11,12-dihydrodiol, a precursor of the ultimate carcinogens, the 11,12-diol-13,14-epoxides, was investigated using eleven human recombinant cytochrome P450s, as well as human lung and liver microsomes. Of all human P450s, 1A1 was the most active in the metabolism of DB[a,l]P (310 pmol/min, nmol P450) and had 5-23-fold higher catalytic activity than other P450s examined. The order of activity in the formation of the 11,12-dihydrodiol was as follows: 1A1 (116 pmol/min, nmol P450) > 2C9 (29) > 1A2 (22) > 2B6 (18) > 3A4 (16) > others (≤ 5). The K(m) of 1A1 for DB[a,l]P and V(max) for the formation of 11,12-dihydrodiol were 3.9 μM and 0.13/min, respectively. Liver microsomes from 14 individuals were shown to metabolize DB[a,l]P and the rates for production of 11,12-dihydrodiol ranged from 4 to 71 pmol/min, nmol P450. Lung microsomes from six organ donors formed the 11,12-dihydrodiol at a rate from 0.1 to 1.3 pmol/min, mg of microsomal protein. These findings describe the potential of individual P450s present in liver and lung to contribute to the metabolic activation and the carcinogenicity of DB[a,l]P.