Isoform-specific induction of a human aldo-keto reductase by polycyclic aromatic hydrocarbons (PAHs), electrophiles, and oxidative stress: implications for the alternative pathway of PAH activation catalyzed by human dihydrodiol dehydrogenase

Cancer Res. 1999 Feb 1;59(3):607-14.

Abstract

Human dihydrodiol dehydrogenase (DD) isoforms are aldo-keto reductases (AKRs) that activate polycyclic aromatic hydrocarbons (PAHs) by oxidizing trans-dihydrodiol proximate carcinogens to reactive and redox-active ortho-quinones. Of these, human AKR1C1 (DD1) and AKR1C2 (DD2) oxidize trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to the cytotoxic and genotoxic metabolite benzo[a]pyrene-7,8-dione (BPQ) with the highest catalytic efficiency. Exposure of HepG2 cells to a panel of inducers revealed that mRNA encoding one or more human AKR1C member(s) was induced (3- to 10-fold) by benzo[a]pyrene and other polycyclic aromatic compounds (bi-functional inducers), electrophilic Michael acceptors and phenolic antioxidants (monofunctional inducers), and reactive oxygen species (ROS). The induction of AKR1C mRNA by bifunctional inducers was delayed with respect to the induction of CYP1A1 mRNA, and AKR1C mRNA was not induced by the nonmetabolizable aryl hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). These data suggest that, in contrast to the CYPs, induction of AKR1C member(s) by PAHs and other bifunctional inducers is mediated indirectly via an antioxidant response element rather than a xenobiotic response element. Immunoblot and enzymatic assays confirmed that the increases in AKR1C mRNA were faithfully translated into functional AKR1C protein(s). The increased DD activity in HepG2 lysates was inhibited only by high concentrations of ursodeoxycholate, which suggested that AKR1C2 (DD2, bile-acid-binding protein) was not the isoform induced. RNase protection assays identified AKR1C1 (DD1) mRNA as the transcript which was up-regulated by mono- and bi-functional inducers and ROS in both human hepatoma (HepG2) and colon carcinoma (HT29) cells. BPQ, the electrophilic and redox-cycling product of the AKR1C1 reaction, also induced AKR1C1 expression. Thus, BPQ formation by AKR1C1 results in both a chemical (redox-cycling) and a genetic (AKR1C1 induction) amplification of ROS in PAH-exposed cells. Because ROS have been implicated in both tumor initiation and tumor promotion, the amplification of ROS by this pathway may play a significant role in PAH carcinogenesis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alcohol Oxidoreductases / antagonists & inhibitors
  • Alcohol Oxidoreductases / biosynthesis*
  • Alcohol Oxidoreductases / metabolism*
  • Aldehyde Reductase
  • Aldo-Keto Reductases
  • Benzopyrenes / pharmacology
  • Benzoquinones / pharmacology
  • Biotransformation
  • Carcinoma, Hepatocellular / enzymology
  • Cytochrome P-450 CYP1A1 / biosynthesis
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • HT29 Cells / enzymology
  • Humans
  • Indicators and Reagents / pharmacology
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / biosynthesis*
  • Isoenzymes / metabolism
  • Ligands
  • Oxidation-Reduction
  • Oxidative Stress / physiology
  • Oxidoreductases Acting on CH-CH Group Donors*
  • Oxidoreductases*
  • Polychlorinated Dibenzodioxins / metabolism
  • Polychlorinated Dibenzodioxins / pharmacology
  • Polycyclic Aromatic Hydrocarbons / pharmacokinetics*
  • Polycyclic Aromatic Hydrocarbons / pharmacology*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / metabolism
  • Receptors, Aryl Hydrocarbon / metabolism
  • Ribonucleases / metabolism
  • Xenobiotics / pharmacology
  • beta-Naphthoflavone / pharmacology

Substances

  • Benzopyrenes
  • Benzoquinones
  • Enzyme Inhibitors
  • Indicators and Reagents
  • Isoenzymes
  • Ligands
  • Polychlorinated Dibenzodioxins
  • Polycyclic Aromatic Hydrocarbons
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Xenobiotics
  • quinone
  • beta-Naphthoflavone
  • benzo(a)pyrene-7,8-dione
  • Oxidoreductases
  • Alcohol Oxidoreductases
  • dihydrodiol dehydrogenases
  • Aldo-Keto Reductases
  • Aldehyde Reductase
  • Cytochrome P-450 CYP1A1
  • Oxidoreductases Acting on CH-CH Group Donors
  • cis-1,2-dihydro-1,2-dihydroxynaphthalene dehydrogenase
  • Ribonucleases