Polycyclic aromatic hydrocarbon/metal mixtures: Effect on PAH induction of CYP1A1 in human HEPG2 cells

Dilip D. Vakharia, Ning Liu, Ronald Pause, Michael Fasco, Erin Bessette, Qing Yu Zhang, Laurence S. Kaminsky

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Environmental polycyclic aromatic hydrocarbons (PAHs) and metals coexist, and such mixtures could affect the carcinogenicity of PAHs, possibly by modification of PAH induction of the PAH-bioactivating CYP1A. The effect on PAH-mediated CYP1A induction of arsenic, lead, mercury, or cadmium (ranked as the most hazardous environmental metals by the Environmental Protection Agency and the Agency for Toxic Substances and Disease Registry) has thus been investigated. Induction of CYP1A1 by benzo[a]pyrene (BAP), benzo[b]fluoranthene (BBF), dibenzo[a,h]anthracene (DBAHA), benzo[a]anthracene (BAA), or benzo[k]fluoranthene (BKF) was probed by ethoxyresorufin-O-deethylase activity (EROD) in 96-well plates of human HepG2 cells, by immunoblot analysis, and by reverse transcription-polymerase chain reaction. Cells rapidly took up PAHs (BAP, BKF) from medium; by 24 h only 14% remained in the medium, and no detectable PAH bound to well walls. Induction efficiency (relative to dimethyl sulfoxide controls) was in the order BKF (16-fold) > DBAHA (14-fold) > BAA (4-fold) > BAP (3-fold) > BBF (1-fold), all at 5 μM PAH. The metals did not markedly affect cell viability at concentrations of arsenic, 5 μ; lead, 50 μM; mercury, 5 μM; and cadmium, 5 μM. At 5 μM PAH concentration, all of the metals decreased levels of PAH-induced CYP1A1 activities (direct inhibition of EROD activity was excluded) by variable extents and in a PAH-dependent manner. With BAP as inducer decreases in induction were arsenic, 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 PAH carcinogenic potential by decreasing PAH-mediated induction of their bioactivation by CYP1A1.

Original languageEnglish (US)
Pages (from-to)999-1006
Number of pages8
JournalDrug Metabolism and Disposition
Volume29
Issue number7
StatePublished - 2001
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Fingerprint

Dive into the research topics of 'Polycyclic aromatic hydrocarbon/metal mixtures: Effect on PAH induction of CYP1A1 in human HEPG2 cells'. Together they form a unique fingerprint.

Cite this