3897

Metabolic activation of polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene, is catalyzed by cytochrome P450 (CYP450) enzymes. The products of these reactions are more electrophilic than their parent compounds and have the ability to bind to cellular macromolecules and exert tumorigenic activity. We have reported previously (Kabler et. al, Proc. Am. Assoc. Cancer Res., 43, p. 593) on the ability of B[a]P or its dihydrodiols to induce cytotoxicity in V79MZ cells stably expressing hCYP1A1. B[a]P and its dihydrodiols are highly cytotoxic in V79MZh1A1 cells (IC50 B[a]P = 0.27 μM; IC50 (+)-B[a]P-7,8-diol = 47 μM, (-)-B[a]P-7,8-diol = 8.1 μM). To further extend the study of the activation of B[a]P and its dihydrodiols to other hCYPs, we utilized V79MZ cell lines stably transfected with the human CYPs 1A2, 1B1, and 3A4 in order to study the cytotoxicity of B[a]P or its individual dihydrodiols enantiomer metabolites in a tightly regulated in vitro cell culture system. V79MZh1B1 cells were moderately sensitive to B[a]P (IC50 = 2.9 μM), representing a 4-fold enhancement of toxicity over the parent V79MZ cells, and demonstrated IC50s of 70 nM and 20 nM for the (+) and (-)-B[a]P-7,8-diols, respectively. V79MZh3A4 cells demonstrated a 5-fold enhancement of toxicity over the parent V79MZ cells with an IC50 of 1.75 μM for B[a]P, while the dihydrodiols exhibited nearly equal cytotoxicity in the presence of this P450 (IC50 = 0.85 μM). V79MZh1A2 cells demonstrated a 20-fold enhanced sensitivity to B[a]P, with an IC50 of 0.39 μM. Cells expressing hCYP1A2 were sensitive to (-)-B[a]P-7,-8-diol cytotoxicity, with 10-fold sensitivity over the parent cell line and an IC50 of 90 nM, but were not sensitive to the (+)-B[a]P7,8-diol (IC50 > 1000 nM) over the dose range tested. These results demonstrate that the toxicity of B[a]P and its metabolites depend upon the P450 expressed, and are of relevance in considering cancer risk for exposure to putative environmental carcinogens among individuals with different P450 expression genotypes.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]