CYP1A1 in polycyclic aromatic hydrocarbon-induced B lymphocyte growth suppression

The AhR is a ligand-activated transcription factor that mediates immunosuppression by environmental PAH. Previous studies demonstrated that activation of mature human B cells up-regulates AhR expression, suggesting that human B cells are direct PAH targets. To test this hypothesis and to determine the metabolic requirements for PAH toxicity in a human model, the effects of a prototypic PAH, B[a]P, on B cell growth were evaluated. B[a]P and its proximal (B[a]P-7,8-dihydrodiol) and terminal (B[a]P-7,8-dihydrodiol-9,10-epoxide) metabolites inhibited growth in a dose-dependent manner. A poorly metabolized AhR ligand had no effect, suggesting that biotransformation is required for growth inhibition. Inhibition of the CYP1A1 monooxygenase completely blocked growth inhibition induced by B[a]P or B[a]P-7,8-dihydrodiol, but not by B[a]P-dihydrodiol-9,10-epoxide, indicating that CYP1A1-dependent metabolism of B[a]P into the terminal B[a]P-7,8-dihydrodiol-9,10-epoxide metabolite is required for growth inhibition. These studies show for the first time the metabolic requirements for PAH-mediated suppression of human B cell growth.