INHIBITION OF SARCOPLASMIC ENDOPLASMIC-RETICULUM CALCIUM ATPASES (SERCA) BY POLYCYCLIC AROMATIC-HYDROCARBONS IN HPB-ALL HUMAN T-CELLS AND OTHER TISSUES

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.