Effect of a standardized complex mixture derived from coal tar on the metabolic activation of carcinogenic polycyclic aromatic hydrocarbons in human cells in culture.
A complex mixture of polycyclic aromatic hydrocarbons (PAH) extracted from coal tar, standard reference material (SRM) 1597, has been shown to initiate tumor formation in mouse initiation-promotion assays in our laboratory [(2001) Carcinogenesis 22 (7), 1077-1086]. To determine the effects of SRM 1597 on PAH activation in human cells, we investigated the PAH-DNA adduct formation in the human mammary carcinoma-derived cell line MCF-7. We examined the effects of SRM 1597 on the metabolic activation to DNA binding derivatives of two carcinogenic PAHs, the bay region containing benzo[a]pyrene (B[a]P) and the more carcinogenic fjord region containing dibenzo[a,l]pyrene (DB[a,l]P). PAH-DNA adduct analysis by 33P-postlabeling and reversed phase high-performance liquid chromatography revealed a significant decrease in the levels of both B[a]P and DB[a,l]P DNA adduct formation on cotreatment with SRM 1597 in comparison to cells exposed to B[a]P or DB[a,l]P alone. However, the inhibition of PAH-DNA adduct formation only occurred within the first 48 h of exposure in cells cotreated with SRM 1597 and B[a]P. In contrast, SRM 1597 significantly inhibited the level of DB[a,l]P DNA adducts throughout the 120 h of exposure. Induction of human cytochrome P450 (P450) enzymes 1A1 and P4501B1 on treatment with SRM 1597 was observed by immunoblots. These results suggest that the important factors in determining the carcinogenic activity of PAH within a complex mixture would depend on the ability of other components of the mixture to promote or inhibit the activation of carcinogenic PAH by the induction of P450 enzymes followed by the formation of DNA adducts.
Mahadevan
Brinda
B
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon 97331, USA.
Marston
Charis P
CP
Dashwood
Wan-Mohaiza
WM
Li
Yonghai
Y
Pereira
Clifford
C
Baird
William M
WM
D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000187:drug effects; D001711:Biotransformation; D002273:Carcinogens / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003033:Coal Tar / Q000737:chemistry* / Q000592:standards*; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis / Q000187:drug effects; D065633:Cytochrome P-450 CYP1B1; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry; D006801:Humans; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity; D013997:Time Factors
D002273:Carcinogens; D018736:DNA Adducts; D011084:Polycyclic Aromatic Hydrocarbons; D003033:Coal Tar; D004247:DNA; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C585498:Cyp1b1 protein, mouse; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1