HUMAN T-CELLS ARE HIGHLY SENSITIVE TO SUPPRESSION OF MITOGENESIS BY POLYCYCLIC AROMATIC-HYDROCARBONS AND THIS EFFECT IS DIFFERENTIALLY REVERSED BY ALPHA-NAPHTHOFLAVONE
Dr. Davila et al., HUMAN T-CELLS ARE HIGHLY SENSITIVE TO SUPPRESSION OF MITOGENESIS BY POLYCYCLIC AROMATIC-HYDROCARBONS AND THIS EFFECT IS DIFFERENTIALLY REVERSED BY ALPHA-NAPHTHOFLAVONE, Toxicology and applied pharmacology, 139(2), 1996, pp. 333-341
The immunosuppressive effects of polycyclic aromatic hydrocarbons (PAH
s) on immune responses in rodents, both in vivo and in vitro, have bee
n widely documented. However, few studies have addressed the immunotox
icity of PAHs in the human system. In this report, we examined the tox
ic effects of nine different PAHs on human peripheral blood T cell mit
ogenesis. We found that benzo(a)pyrene (BaP), 3-methylcholanthrene (3-
MC), and 7,12-dimethylbenz(a)anthracene (DMBA) were highly immunotoxic
in the human system, while dibenz(a,c)anthracene (DAC) and dibenz(a,h
)anthracene (DAH) were of intermediate toxicity, 9,10-dimethylanthrace
ne (DMA), benzo(e)pyrene (BeP), and benz(a)anthracene (BA) were mildly
immunotoxic, and anthracene (ANTH) had no measureable toxicity at the
concentrations tested. Our results using human lymphocytes differed f
rom previous studies in rodents, in that BaP and 3-MC were the most im
munotoxic PAHs in the human mitogenesis assay, while DMBA has long bee
n regarded as the PAH that is most potently toxic to rodent T cell res
ponses. We also showed that alpha-naphthoflavone (ANF), which function
s as both an Ah receptor antagonist and an inhibitor of cytochrome P45
0 activity, was able to block the suppressive effects of both BaP and
DMBA, but not 3-MC. This suggests that the immunotoxicity of 3-MC may
be mediated through a different mechanism than BaP or DMBA. Addition o
f four different BaP metabolites directly to cultures of human mononuc
lear cells showed that the 7,8-dihydrodiol metabolite was the most tox
ic, and that this toxicity could be completely blocked by equimolar an
d 10-fold greater concentrations of ANF. The 7,8-dihydrodiol metabolit
e was probably further metabolized to the 7,8-diol epoxide, the toxici
ty of which could not be effectively reversed by ANF. The 4,5-epoxide
metabolite was apparently cytotoxic at high concentrations (10 mu M),
while the 7-hydroxy metabolite had no overtly negative effects on prol
iferation. (C) 1996 Academic Press, Inc.