Polycyclic aromatic hydrocarbon/metal mixtures: Effect on PAH induction ofCYP1A1 in human HEPG2 cells

Citation
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
Citations number
41
Categorie Soggetti
Pharmacology & Toxicology
Journal title
DRUG METABOLISM AND DISPOSITION
ISSN journal
00909556 → ACNP
Volume
29
Issue
7
Year of publication
2001
Pages
999 - 1006
Database
ISI
SICI code
0090-9556(200107)29:7<999:PAHMEO>2.0.ZU;2-J
Abstract
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.