Carcinogenesis, Vol 18, 167-175, Copyright © 1997 by Oxford University Press
J Cheu, G Talaska, M Miller, C Rice and D Warshawsky
Ferric oxide (Fe2O3) and aluminum oxide (Al2O3) particles are widely
encountered in occupational settings. Benzo[a]pyrene (B[a]P), a well-
characterized environmental carcinogen, is frequently adsorbed onto
particles. It has been shown that B[a]P-coated Fe2O3 particles (B[a]P-
Fe2O3) significantly increased lung tumors in the hamster in contrast to
B[a]P-coated Al2O3 (B[a]P-Al2O3) or B[a]P alone. In order to determine the
genotoxic effects of these particles on the metabolism of B[a]P, pulmonary
alveolar macrophages (AM) from male Syrian golden hamsters were incubated
with 5 microg (19.8 nmol) B[a]P-coated respirable size (99% < 5 microm)
Fe2O3 and Al2O3 particles with loads from 0.5 to 2.0 mg. Intracellular
uptake of B[a]P by AM at 24 h was higher with B[a]P-Fe2O3 than that of
B[a]P alone (P < 0.05) or B[a]P- Al2O3 (P < 0.05). Total B[a]P
metabolism was significantly greater in AM exposed to B[a]P-coated Fe2O3 at
1.0 and 1.5 mg than in the AM exposed to B[a]p-al2O3 (0.5, 1.0 and 1.5 mg)
(P < 0.05) or B[a]P alone (P < 0.05). Similar significant differences
for Fe2O3 relative to Al2O3 and B[a]P alone were also apparent for total
dihydrodiols, quinones and phenolic metabolites. Co-administration of 5
microg alpha- naphthoflavone (alpha-NF, an inhibitor of cytochrome P-4501A1
and P- 4501A2) and 10(-3) M cyclohexene oxide (CO, an inhibitor of epoxide
hydrolase) significantly reduced B[a]P metabolism in B[a]P-Fe2O3 (P <
0.05) and B[a]P-Al2O3 (P < 0.05) treated groups relative to B[a]P alone.
AM were co-cultured with hamster tracheal epithelial cells (HTE) and
treated as described above for metabolism studies to assess the DNA binding
of B[a]P metabolites in the target cells, using 32P- postlabeling
techniques. Two adducts were observed that had chromatographic behavior
similar to 7R,8S,9S-trihydroxy-10R-(N2-
deoxyguanosyl-3'-phosphate)-7,8,9,10-t etrahydrobenzo[a]pyrene [(+)-
anti-BPDE-dG, adduct 1, major adduct representing 70-80% of total adducts]
and 7S,8R,9R-trihydroxy-10S-(N2-deoxyguanosyl-3'-phosphate)- 7,8,9,10-t
etrahydrobenzo[a]pyrene [(-)-anti-BPDE-dG, adduct 2, representing 20-30% of
total adducts]. B[a]P-Fe2O3 treatment enhanced the levels of the two
B[a]P-DNA adducts in the HTE compared with B[a]P- Al2O3 (P < 0.05) or
B[a]P alone. The inhibitors alphaNF and CO significantly reduced total
adduct levels in the HTE (P < 0.05) in the B[a]P and B[a]P-Fe2O3
treatments as well as adduct 1 and adduct 2 levels. Our data suggest that
the cocarcinogenic effect of B[a]P-Fe2O3 relative to B[a]P-coated Al2O3 can
be due to: (i) the enhancement of B[a]P metabolism in AM by Fe2O3
associated with the increased uptake of B[a]P; and (ii) augmentation of DNA
adduct formation in epithelial cells.
ARTICLES
Benzo[a]pyrene coated ferric oxide and aluminum oxide particles: uptake, metabolism and DNA binding in hamster pulmonary alveolar macrophages and tracheal epithelial cells in vitro [published erratum appears in Carcinogenesis 1997 May;18(5):1123]
Department of Environmental Health, University of Cincinnati, OH 45267- 0056, USA.
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