Alterations in Human B Cell Calcium Homeostasis by Polycyclic Aromatic Hydrocarbons: Possible Associations with Cytochrome P450 Metabolism and Increased Protein Tyrosine Phosphorylation

• Published in: Toxicology and applied pharmacology Vol. 149; no. 1; pp. 80 - 89
• Main Authors: Mounho, Barbara J., Burchiel, Scott W.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.03.1998; Elsevier
• Subjects: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - toxicity; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Benzo(a)pyrene - metabolism; Benzo(a)pyrene - toxicity; Benzoflavones - pharmacology; Benzoquinones; Biological and medical sciences; Calcium - metabolism; Cell Line; Chemical and industrial products toxicology. Toxic occupational diseases; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Dihydroxydihydrobenzopyrenes - toxicity; humanB cells; Humans; immunotoxicity; intracellular Ca2; Lactams, Macrocyclic; Medical sciences; polycyclic aromatic hydrocarbons; protein tyrosine kinases; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Quinones - pharmacology; Rifabutin - analogs & derivatives; signaltransduction; Toxicology; Various organic compounds; intracellular Ca2; signaltransduction; protein tyrosine kinases; humanB cells; immunotoxicity; cytochrome P450; polycyclic aromatic hydrocarbons; Human; Tyrosine; Immunopathology; Phosphorylation; Toxicity; Cytochrome P450; B-Lymphocyte; Calcium Ions; Polycyclic aromatic compound; In vitro; Signal transduction; Intracellular; Mechanism of action; Humoral immunity
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.1997.8345

Previous studies performed in this laboratory have shown that certain benzo(a)pyrene (BaP) metabolites, such as benzo(a)pyrene-7,8-dihydrodiol (BaP-7,8-diol) and benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), were more effective in elevating intracellular Ca2+in normal human peripheral blood mononuclear cell (HPBMC) T and B cells than was BaP. Additionally, it has been shown that the suppression of human T cell mitogenesis produced by polycyclic aromatic hydrocarbons (PAHs) and certain BaP metabolites is reversed by treatment with α-naphthoflavone (ANF), a cytochrome P450 1A and 1B inhibitor. ANF also diminishes the elevation in intracellular calcium (Ca2+) produced by BaP in HPBMC. In the present studies, we further defined the relationships between intracellular Ca2+elevation produced by BaP and two immunotoxic P450-derived metabolites, BaP-7,8-diol and BPDE in the Daudi human B cell line. At 1, 4, and 18 h, both BaP-7,8-diol and BPDE produced a significant rise in intracellular Ca2+. This effect, however, was not observed with BaP or benzo(e)pyrene (BeP), a nonimmunotoxic PAH. To evaluate the potential role of cytochrome P450 metabolism in PAH-induced Ca2+elevation, Daudi cells were pretreated with ANF for 4 h, followed by treatment with BaP metabolites for 18 h. ANF completely reversed the rise in Ca2+produced by BaP-7,8-diol, but had no effect on the Ca2+elevation produced by BPDE. These results suggest that BPDE may be the ultimate P450 metabolite responsible for Ca2+elevation in human B cells. BaP-7,8-diol and BPDE were found to increase tyrosine phosphorylation in Daudi whole cell lysates and to increase tyrosine phosphorylation of two important Src-related protein tyrosine kinases (PTKs), Lyn and Syk. Inhibition of tyrosine phosphorylation by herbimycin A was found to largely prevent the increase in intracellular Ca2+produced by BaP-7,8-diol and BPDE, suggesting that Ca2+elevation is coupled to increased tyrosine phosphorylation in Daudi. BPDE was found to produce a statistically significant increase in tyrosine phosphorylation of Lyn and Syk within 10 min of exposure. Collectively, these data demonstrate that certain P450-derived metabolites of BaP may be responsible for PTK activation and an increase intracellular Ca2+, which may alter antigen receptor signaling in human B cells.