Protein tyrosine kinase activation by polycyclic aromatic hydrocarbons in human HPB-ALL T cells.
It has been well established that certain polycyclic aromatic hydrocarbons (PAHs), such as 7,12-dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (3MC), and benzo[a]pyrene (BaP), produce immunotoxicity and cancer in rodents and that these effects are also likely seen in humans. Our laboratory has found that polycyclic aromatic hydrocarbons (PAHs) produce an increase in intracellular Ca2+ in lymphocytes that appears to correlate with their immunotoxicity. Specifically, immunotoxic PAHs, such as DMBA and BaP, have been shown to produce a sustained increase in intracellular Ca2+ in lymphocytes, whereas nonimmunosuppressive PAHs, such as benzo[e]pyrene (BeP) and anthracene, do not. Our studies previously demonstrated that the rapid increase in intracellular Ca2+ produced by DMBA in HPB-ALL T cells was caused by protein tyrosine kinase (PTK) activation in human T cells, leading to tyrosine phosphorylation of phospholipase C (PLCgamma) and IP3-dependent Ca2+ mobilization. However, the specificity of PTK activation by PAHs was not established. In the present studies, we extend our observations of PTK activation by examining a number of PAHs for their effects on total and specific (Fyn and ZAP-70) PTK activity. We show that 10 microM concentrations of PAHs nonspecifically and rapidly (within 5 min) stimulate PTKs in the HPB-ALL human T cell line. BeP and anthracene were found to be nearly as effective at increasing total tyrosine kinase activity as DMBA, 3MC, and BaP, observed 5 min after exposure. We found that only immunotoxic PAHs activated the Fyn and ZAP-70 PTKs at 10 min, but total PTK activity was still increased by nonimmunotoxic PAHs, BeP, or anthracene after 10 min of exposure. These studies demonstrate that immunotoxic PAHs increase total and specific PTK activity in the human HPB-ALL T cell line. Thus the rapid increase in PTK activity produced by PAHs may not correlate with the immunotoxicity of these agents.
Davila
D R
DR
Toxicology Program, University of New Mexico College of Pharmacy, Albuquerque 87131, USA.
Lane
J L
JL
Lauer
F T
FT
Burchiel
S W
SW
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000704:Analysis of Variance; D000873:Anthracenes / Q000494:pharmacology; D001564:Benzo(a)pyrene / Q000494:pharmacology; D001580:Benzopyrenes / Q000494:pharmacology; D002274:Carcinogens, Environmental / Q000494:pharmacology*; D002460:Cell Line; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000187:drug effects* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000873:Anthracenes; D001580:Benzopyrenes; D002274:Carcinogens, Environmental; D011084:Polycyclic Aromatic Hydrocarbons; D001564:Benzo(a)pyrene; D015127:9,10-Dimethyl-1,2-benzanthracene; C026487:benzo(e)pyrene; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); C034020:anthracene