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Alterations in human B cell calcium homeostasis by polycyclic aromatic hydrocarbons: possible associations with cytochrome P450 metabolism and increased protein tyrosine phosphorylation.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 1998 Mar; Vol. 149 (1), pp. 80-9. - Publication Year :
- 1998
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Abstract
- 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 alpha-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.
- Subjects :
- 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide toxicity
B-Lymphocytes metabolism
Benzo(a)pyrene metabolism
Benzoflavones pharmacology
Benzoquinones
Cell Line
Cytochrome P-450 Enzyme Inhibitors
Dihydroxydihydrobenzopyrenes toxicity
Humans
Lactams, Macrocyclic
Protein-Tyrosine Kinases antagonists & inhibitors
Quinones pharmacology
Rifabutin analogs & derivatives
B-Lymphocytes drug effects
Benzo(a)pyrene toxicity
Calcium metabolism
Cytochrome P-450 Enzyme System metabolism
Protein-Tyrosine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0041-008X
- Volume :
- 149
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 9512730
- Full Text :
- https://doi.org/10.1006/taap.1997.8345