Metabolic activation of the potent carcinogen dibenzo[a,l]pyrene by human recombinant cytochromes P450, lung and liver microsomes.
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 (< or = 5). The Km of 1A1 for DB[a,l]P and Vmax for the formation of 11,12-dihydrodiol were 3.9 microM 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.
Shou
M
M
Laboratory of Molecular Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Krausz
K W
KW
Gonzalez
F J
FJ
Gelboin
H V
HV
D000293:Adolescent; D000328:Adult; D001580:Benzopyrenes / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D008875:Middle Aged; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
D001580:Benzopyrenes; D002273:Carcinogens; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; C041517:dibenzo(a,l)pyrene