Dd. Vakharia et al., Polycyclic aromatic hydrocarbon/metal mixtures: Effect on PAH induction ofCYP1A1 in human HEPG2 cells, DRUG META D, 29(7), 2001, pp. 999-1006
Environmental polycyclic aromatic hydrocarbons (PAHs) and metals coexist, a
nd such mixtures could affect the carcinogenicity of PAHs, possibly by modi
fication of PAM induction of the PAH-bioactivating CYP1A. The effect on PAM
-mediated CYP1A induction of arsenic, lead, mercury, or cadmium (ranked as
the most hazardous environmental metals by the Environmental Protection Age
ncy and the Agency for Toxic Substances and Disease Registry) has thus been
investigated. Induction of CYP1A1 by benzo[a]pyrene (BAP), benzo[b]fluoran
thene (BBF), dibenzo[a,h]anthracene (DBAHA), benzo[a]anthracene (BAA), or b
enzo[k]fluoranthene (BKF) was probed by ethoxyresorufin-O-deethylase activi
ty (EROD) in 96-well plates of human HepG2 cells, by immunoblot analysis, a
nd by reverse transcription-polymerase chain reaction. Cells rapidly took u
p PAHs (BAP, BKF) from medium; by 24 h only 14% remained in the medium, and
no detectable PAM bound to well walls. Induction efficiency (relative to d
imethyl sulfoxide controls) was in the order BKF (16-fold)> DBAHA (14-fold)
> BAA (4-fold) > BAP (3-fold) > BBF (1-fold), all at 5 muM PAM. The metals
did not markedly affect cell viability at concentrations of arsenic, 5 muM
; lead, 50 muM; mercury, 5 muM; and cadmium, 5 muM. At 5 muM PAM concentrat
ion, all of the metals decreased levels of PAM-induced CYP1A1 activities (d
irect inhibition of EROD activity was excluded) by variable extents and in
a PAM-dependent manner. With BAP as inducer decreases in induction were ars
enic, 57%; cadmium, 82%; mercury, 4%; and lead, 20%. The decreases were not
a consequence of transcriptional down-regulation. One possible conclusion
is that these metals could diminish PAM carcinogenic potential by decreasin
g PAM-mediated induction of their bioactivation by CYP1A1.