Effect of a Standardized Complex Mixture Derived from Coal Tar on the Metabolic Activation of Carcinogenic Polycyclic Aromatic Hydrocarbons in Human Cells in Culture

Abstract

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.

The influence of diesel exhaust on polycyclic aromatic hydrocarbon-induced DNA damage, gene expression, and tumor initiation in Sencar mice in vivo

“…Although PAHs are typically found in complex mixtures, much of the PAH research has focused on the effects of individual, potent carcinogenic member compounds such as BP or DBP. Due to difficulties and uncertainties in scientific evaluation, limited research has been done on binary or artificial mixtures [19][20][21][22][23][24], and to a lesser extent on complex mixtures [25][26][27]. These previous studies have focused primarily on the genotoxic effects of PAHs (e.g.…”

Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

“…The results suggest that these PAHs inhibit second step of metabolic activation of these dihydrodiols to DNA-damaging products as well as first step of metabolism (by measuring inhibition of EROD activitiy) (20). Thus, individual PAHs may affect their own and metabolism of other carcinogens catalyzed by CYP1A1, 1A2, and 1B1, and these phenomena may cause alteration in their ability to transform cells when single or complex PAH mixtures are ingested by mammals, influencing risk assessment (113)(114)(115)(116)(117).…”

“…Since human CYP1B1 protein was not expressed in yeast and Escherichia coli and charactered until 1994-1997 (16,104,110,111), studies on the comparison of selectivities of xenobiotic inhibitors for CYP1A1, 1A2, and 1B1 were examined in 1998 by us (112) and by other investigators (113)(114)(115)(116)(117). We first examined total of 24 polycyclic hydrocarbons, many containing acetylenic side chains for their abilities to inhibit 7-ethoxyresorufin Odeethylation activities catalyzed by human CYP1A1, 1A2, and 1B1 (112).…”

Quantitative Assessment of Polycyclic Aromatic Hydrocarbons and Heavy Metals in Fish Roasted with Firewood, Waste Tyres and Polyethylene Materials

“…PAHs in the environment have become serious concern worldwide since the exposure to high concentrations has been linked to carcinogenic risk [6]. The routes of exposure to PAHs are from inhalation of ambient and indoor air, exhaust fumes or ingestion of food [1,2,7,8].…”