Metabolic interactions between low doses of benzo[a]pyrene and tributyltin in arctic charr (Salvelinus alpinus): a long-term in vivo study

Toxicol Appl Pharmacol. 2003 Oct 1;192(1):45-55. doi: 10.1016/s0041-008x(02)00042-x.


We have previously reported that short-term, single exposure to a high dose of tributyltin (TBT), a widely used antifouling biocide, inhibited both the in vivo metabolism and metabolic activation of the carcinogenic polycyclic aromatic hydrocarbon benzo[a]pyrene (BaP) in fish; (BaP), in turn, stimulated TBT metabolism. Here, we provide further mechanistic evidence of mutual metabolic interactions between BaP and TBT in response to long-term, repeated exposures to low doses. Juvenile Arctic charr (Salvelinus alpinus) received 10 separate i.p. injections (a single injection every 6 days) of BaP (3 mg/kg), TBT (0.3 mg/kg), or both in combination; control fish received corn oil vehicle only. Two days after the 2nd (Day 8), 6th (Day 32), and 10th dose (Day 56), blood, bile, and liver samples were collected and analyzed for a suite of biomarkers. HPLC/fluorescence analysis indicated that TBT cotreatment inhibited the formation of (+)-anti-BaP diol-epoxide adducts with plasma albumin (53%, Day 8), hepatic DNA (27%, Day 32), or both albumin and globin (50 and 58%, Day 56) compared to BaP alone. This antagonistic interaction was associated with a time-dependent modulation (inhibition at Day 8, enhancement at Day 32) of both cytochrome P450 (P450)1A-mediated ethoxyresorufin O-deethylase (EROD) activity and biliary BaP metabolite formation. TBT cotreatment also inhibited (39%) the BaP-mediated induction of hepatic glutathione S-transferase (GST) activity observed at Day 8. Treatment with TBT alone increased EROD activity (60%) at Day 32, but decreased both GST activity (70 and 37%) and glutathione content (24% and 16%) at Days 32 and 56, respectively. GC/MS analysis revealed that, at Day 56, BaP cotreatment increased (200%) the levels of biliary butyltin compounds, including mono- and dibutyltin metabolites. This potentiative interaction was associated with a protective effect of BaP cotreatment against the TBT-mediated decreases in GST activity and glutathione content. The current results demonstrate that, whereas TBT inhibited BaP bioactivation via a time-dependent modulation of P4501A induction, BaP stimulated the Phase II metabolism of TBT and/or its biliary excretion. The mutual metabolic interactions between these two widespread aquatic pollutants reinforce the need for long-term in vivo interactive studies at low doses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / metabolism
  • Animals
  • Benzo(a)pyrene / pharmacokinetics*
  • Bile / metabolism
  • Biotransformation
  • Cytochrome P-450 CYP1A1 / metabolism
  • Cytosol / metabolism
  • DNA / biosynthesis
  • DNA / isolation & purification
  • Drug Interactions
  • Environmental Pollutants / pharmacokinetics*
  • Globins / metabolism
  • Glutathione / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Receptors, Glucocorticoid / metabolism
  • Spectrophotometry, Ultraviolet
  • Trialkyltin Compounds / pharmacokinetics*
  • Trout / metabolism*


  • Albumins
  • Environmental Pollutants
  • Receptors, Glucocorticoid
  • Trialkyltin Compounds
  • Benzo(a)pyrene
  • tributyltin
  • Globins
  • DNA
  • Cytochrome P-450 CYP1A1
  • Glutathione