ToxSci Advance Access originally published online on July 27, 2005
Toxicological Sciences 2005 87(2):419-426; doi:10.1093/toxsci/kfi265
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Ryanodine Receptor-Mediated Rapid Increase in Intracellular Calcium Induced by 7,8-Benzo(a)Pyrene Quinone in Human and Murine Leukocytes
* The University of New Mexico College of Pharmacy Toxicology Program, Albuquerque, New Mexico 87131–0001; University of California at Davis, Dept. of VM:Molecular Biosciences, and Center for Children's Environmental Health, Davis, California 95616; and The University of Pennsylvania School of Medicine, Department of Pharmacology, Philadelphia, Pennsylvania 19104–6084
Received June 16, 2005; accepted July 14, 2005
Benzo(a)pyrene (BaP) is an environmentally prevalent polycyclic aromatic hydrocarbon (PAH) known to produce immunotoxicity in murine and human lymphocytes. Previous studies by our lab have shown that certain BaP metabolites increase intracellular Ca2+ in human and murine lymphocytes. The mechanism by which these BaP metabolites increase Ca2+ may involve src kinase activation and mitochondrial oxidative stress. We have implicated a new pathway of Ca2+ elevation in lymphocytes produced by a novel BaP metabolite, BaP-7,8-dione (7,8-BPQ). This ortho quinone is produced from BaP-7,8-dihydrodiol by aldoketoreductase 1C1 (AKR1C) isoforms in human cells. We have previously shown that 7,8-BPQ increases Ca2+ levels in an in vitro rabbit skeletal muscle sarcoplasmic reticulum (SR) vesicle model via interaction with ryanodine receptors (RyR). In the present study, we found that 7,8-BPQ produced a RyR-dependent rapid increase in intracellular Ca2+ in the Daudi human B cell line. However, other BP-diones including 1,6-, 3,6-, and 6,12-BPQs failed to produce a rapid increase in Ca2+. Instead they produced a late increase in intracellular Ca2+, presumably via a redox-cycling-dependent loss of Ca2+ buffering capacity by mitochondria. Functional RyR were detected in Daudi using a 3H-ryanodine binding assay. The studies were extended to normal human peripheral blood and murine spleen cells, where it was found that 7,8-BPQ rapidly elevated intracellular Ca2+ in B cells and T cells in both species. The Ca2+-elevating effect of 7,8-BPQ was prevented by pretreatment with a high concentration of ryanodine (500 µM). Collectively, these results demonstrate a novel mechanism of Ca2+ elevation by an environmentally relevant metabolite of BaP in murine and human lymphocytes.
Key Words: ryanodine receptor; calcium; 7,8-benzo(a)pyrene quinone.
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