Metabolism and mutagenicity of dibenzo[a,e]pyrene and the very potent environmental carcinogen dibenzo[a,l]pyrene

Abstract

Dibenzo[a,l]pyrene (DB[a,l]P) is one of the most potent carcinogens ever tested in mouse skin and rat mammary gland. DB[a,l]P is present in cigarette smoke and, presumably, in other environmental pollutants. Metabolism and mutagenicity studies of this compound compared to the weak carcinogen dibenzo[a,e]pyrene (DB[a,e]P) can provide preliminary evidence on its mechanism of carcinogenesis. The mutagenicity of DB[a,l]P, DB[a,e]P, and benzo[a]pyrene (BP) was compared in the Ames assay with Aroclor-induced rat liver S-9. BP was the strongest mutagen. In strain TA100, DB[a,l]P and DB[a,e]P were marginally mutagenic. In strain TA98 both compounds were mutagenic, and DB[a,l]P induced more than twice as many revertants as DB[a,e]P. The mutagenicity of DB[a,l]P does not correlate with its carcinogenicity, since DB[a,l]P is a much stronger carcinogen, but a much weaker mutagen, than BP. The NADPH-supported metabolism of DB[a,e]P and DB[a,l]P was conducted with uninduced and 3-methylcholanthrene-induced rat liver microsomes. Metabolites were analyzed by reverse-phase HPLC and identified by NMR, UV, and mass spectrometry. Uninduced microsomes produced only traces of metabolites with either compound. The major metabolites of DB[a,l]P with induced microsomes were DB[a,l]P 8,9-dihydrodiol, DB[a,l]P 11,12-dihydrodiol, 7-hydroxyDB[a,l]P, and a DB[a,l]P dione. The metabolites of DB[a,e]P with induced microsomes were DB[a,e]P 3,4-dihydrodiol, 3-hydroxyDB[a,e]P, 7-hydroxyDB[a,e]P, and 9-hydroxyDB[a,e]P. Some of these metabolites are very useful in assessing possible pathways of activation in the initiation of cancer.

The Role of Cytochrome P450 1B1 in Dibenzo[ a,l ]pyrene-induced Carcinogenesis

“…Metabolism and DNA binding studies with different cell lines including human mammary carcinoma MCF-7 cells (11)(12)(13) or liver preparations from rats pretreated with different inducers of cytochrome P450 (P450) enzymes such as 3-methylcholanthrene (14,15) or Aroclor 1254 (16) revealed that DB[a,l]P is preferentially activated to its fjord region (−)-anti-11,12-diol 13,14-epoxide (DB[a,l]PDE) by intermediate formation of the corresponding precursor, the (−)-trans-11,12-diol ( Figure 1). …”

Relating aromatic hydrocarbon-induced DNA adducts and c-H-ras mutations in mouse skin papillomas: the role of apurinic sites.

“…DB[a,l]P, DB[a,l]P-11,12-dihydrodiol, DB[a,l]P-8,9-dihydrodiol, and anti-DB[a,l]P diol epoxide (anti-DB[a,l]PDE) were studied because DB[a,l]P is the most potent carcinogenic PAH (18,19) and these two dihydrodiols are major metabolites formed by rat liver microsomes (20). The 11,12-dihydrodiol is the proximate metabolite in the diol epoxide pathway and is almost as potent as DB[a,l]P (19).…”

In Vitro Metabolism of Dibenzo[a,l]pyrene, 2-Chlorodibenzo [a,l]pyrene and 10-Chlorodibenzo[a,l]pyrene - Effects of Chloro Substitution

“…The HPLC profile of DB[a,l]P is shown in Figure 1A. The chromatographic peak eluted at 58 min was the recovered substrate, DB[a,l]P. Based on comparison of their UV-Visible absorption, mass, and NMR spectra with the previously published data [11,21] The metabolites of 2-Cl-DB[a,l]P were separated by HPLC ( Figure 1B). Again, based on UV- Figure 1C).…”

“…Dibenzo[a,l]pyrene (DB[a,l]P) is an environmental contaminant exhibiting tumorigenicity much higher than benzo[a]pyrene. Its metabolic activation and DNA adduct formation have been widely studied [8][9][10][11][12][13][14][15][16][17].…”