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.
Allan
Lenka L
LL
Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118, USA.
Schlezinger
Jennifer J
JJ
Shansab
Maryam
M
Sherr
David H
DH
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D011721:Pyrenes / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism
C402363:1-(1-propynyl)pyrene; D008024:Ligands; D011084:Polycyclic Aromatic Hydrocarbons; D011721:Pyrenes; D018336:Receptors, Aryl Hydrocarbon; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D019363:Cytochrome P-450 CYP1A1