Effect of metals on polycyclic aromatic hydrocarbon induction of CYP1A1 and CYP1A2 in human hepatocyte cultures

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

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Environmental cocontamination by polycyclic aromatic hydrocarbons (PAHs) and metals could affect the carcinogenic consequences of PAH exposure by modifying PAH induction of PAH-bioactivating CYP1A. The effect of As, Pb, Hg, or Cd (ranked as the most hazardous environmental metals by EPA and ATSDR) on CYP1A1 and 1A2 induction by benzo[a]pyrene (BaP), benzo[b]fluoranthene (BbF), dibenzo[a,h]anthracene (DBahA), benzo[a]anthracene (BaA), and benzo[k]fluoranthene (BkF) has thus been investigated in fresh human hepatocyte cultures. Induction was probed by ethoxyresorufin-O-deethylase activity, by immunoblots, and by RT-PCR. Uptake of PAHs into the hepatocytes varied according to PAH and liver donor: 84% of 5 μM BaA and 25-40% of 5 μM DBahA was taken up in 24 h. Hepatocytes retained viability up to 1 μM Cd and 5 μM Pb, Hg, or As and 5 μM PAHs. PAH induction of CYP1A in hepatocytes was variable, some cultures expressed CYP1A1 and others CYP1A1 and 1A2, and to variable extents. Induction efficiency (relative to DMSO controls) at 2.5 μM PAH concentration was in the order BkF (7.6-fold) > DBahA (6.1 fold) > BaP (5.7 fold) > BbF (3.9-fold) > BaA (2.5-fold). All four metals (1-5 μM) decreased CYP1A1/1A2 induction by some of the PAHs with dose-, metal-, and PAH-dependency. Arsenic (5 μM) decreased induction by 47% for BaP, 68% for BaA, 45% for BbF, 79% for BkF, and 53% for DBahA. Induced CYP1A2 protein was much more extensively decreased than 1A1 protein, and CYP1A2 mRNA and, to variable extents, CYP1A1 mRNA were decreased by As. Thus the metals in PAH/ metal mixtures could diminish PAH carcinogenicity by decreasing induction of their bioactivation by CYP1A1/1A2.

Original languageEnglish (US)
Pages (from-to)93-103
Number of pages11
JournalToxicology and Applied Pharmacology
Volume170
Issue number2
DOIs
StatePublished - Jan 15 2001
Externally publishedYes

Keywords

  • Arsenite
  • Cadmium
  • CYP1A1
  • CYP1A2
  • Human hepatocytes
  • Induction
  • Lead
  • Mercury
  • Mixtures
  • Polycyclic aromatic hydrocarbons

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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