INHIBITION OF SARCOPLASMIC ENDOPLASMIC-RETICULUM CALCIUM ATPASES (SERCA) BY POLYCYCLIC AROMATIC-HYDROCARBONS IN HPB-ALL HUMAN T-CELLS AND OTHER TISSUES
Ja. Krieger et al., INHIBITION OF SARCOPLASMIC ENDOPLASMIC-RETICULUM CALCIUM ATPASES (SERCA) BY POLYCYCLIC AROMATIC-HYDROCARBONS IN HPB-ALL HUMAN T-CELLS AND OTHER TISSUES, Toxicology and applied pharmacology, 133(1), 1995, pp. 102-108
Polycyclic aromatic hydrocarbons (PAHs) are immunosuppressive chemical
s found in the environment that have been shown to disrupt intracellul
ar Ca2+ homeostasis and Ca2+-dependent signaling in human and murine l
ymphocytes. Many PAHs produce a rapid and sustained increase in intrac
ellular free Ca2+ in lymphocytes. The mechanism of persistent Ca2+ per
turbation remains undefined. In the present studies, ATP-dependent Ca-
45(2+) uptake into vesicles prepared from a 15,000g supernatant of HPB
-ALL human T cell lysates was significantly inhibited by 0.1, 1, and 1
0 mu M concentrations of the immunotoxic PAHs 7,1 2-dimethylbenz[a]ant
hracene (DMBA), benzo[a]pyrene (BAP), benz[a]anthracene, and 9,10-dime
thylanthracene, but not by the less immunotoxic compounds anthracene (
ANT) and benzo[e]pyrene (BEP). Ca2+-ATPase catalytic activity was dete
rmined by quantitating hydrolysis of ATP in the presence or absence of
PAHs, with known ATPase inhibitors included as controls. Formation of
inorganic phosphate was significantly decreased (>65% of control at 1
0 mu M) by DMBA and BAP, whereas ANT and BEP caused only a slight redu
ction in activity (10% of control at 10 mu M). Anthracene partially re
versed the inhibitory effect of DMBA and BAP on ATP hydrolysis when ag
ents were coincubated. Both DMBA and BAP, but not ANT and BEP, inhibit
ed the activity of all known SERCA-type Ca2+-ATPases, while not affect
ing either Na+, K+-ATPase activity or plasma membrane Ca2+-ATPase acti
vities. These results demonstrate that immunotoxic and carcinogenic po
lycyclic aromatic hydrocarbons have a thapsigargin-like effect in huma
n lymphocytes and SERCA-containing tissues from various species. Inhib
ition of SERCA activity may play an important role in altered Ca2+ hom
eostasis in lymphocytes and other tissues. (C) 1995 Academic Press, In
c.