Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 419-426 |
| Number of pages | 8 |
| Journal | Toxicological Sciences |
| Volume | 87 |
| Issue number | 2 |
| DOIs | |
| State | Published - Oct 2005 |
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Keywords
- 7,8-benzo(a)pyrene quinone
- Calcium
- Ryanodine receptor
ASJC Scopus subject areas
- Toxicology
Cite this
Ryanodine receptor-mediated rapid increase in intracellular calcium induced by 7,8-Benzo(a)Pyrene quinone in human and murine leukocytes. / Gao, Jun; Voss, Andrew A.; Pessah, Isaac N; Lauer, Fredine T.; Penning, Trevor M.; Burchiel, Scott W.
In: Toxicological Sciences, Vol. 87, No. 2, 10.2005, p. 419-426.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ryanodine receptor-mediated rapid increase in intracellular calcium induced by 7,8-Benzo(a)Pyrene quinone in human and murine leukocytes
AU - Gao, Jun
AU - Voss, Andrew A.
AU - Pessah, Isaac N
AU - Lauer, Fredine T.
AU - Penning, Trevor M.
AU - Burchiel, Scott W.
PY - 2005/10
Y1 - 2005/10
N2 - 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.
AB - 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.
KW - 7,8-benzo(a)pyrene quinone
KW - Calcium
KW - Ryanodine receptor
UR - http://www.scopus.com/inward/record.url?scp=24944582207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=24944582207&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfi265
DO - 10.1093/toxsci/kfi265
M3 - Article
C2 - 16049270
AN - SCOPUS:24944582207
VL - 87
SP - 419
EP - 426
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -