Differential expression of cytochrome P450 genes between bromadiolone-resistant and anticoagulant-susceptible Norway rats: a possible role for pharmacokinetics in bromadiolone resistance

Research output: Contribution to journalJournal articlepeer-review

  • Mette Drude Kjær Markussen
  • Ann-Charlotte Heiberg
  • Fredholm, Merete
  • Michael Kristensen
Background: Anticoagulant resistance in Norway rats, Rattus norvegicus (Berk.), has been suggested to be conferred by mutations in the VKORC1 gene, encoding the target protein of anticoagulant rodenticides. Other factors, e.g. pharmacokinetics, may also contribute to resistance, however. To examine the involvement of pharmacokinetics in bromadiolone resistance in male and female rats, liver expression profiles of seven cytochrome P450 genes from a Danish bromadiolone-resistant rat strain (with an Y139C->VKORC1 mutation) were compared with profiles from an anticoagulant-susceptible strain.
Results: In the presence of bromadiolone, the Cyp2e1, Cyp2c13, Cyp3a2 and Cyp3a3 genes were significantly overexpressed, while Cyp2c12 expression was suppressed in resistant female rats compared with susceptible females. relative to susceptible males, resistant males showed significant overexpression of the Cyp2a1, Cyp2e1, Cyp3a2 and Cyp3a3 genes. On exposure to bromadiolone, females had higher Cyp2e1 expression than males, which possibly explains why female rats are generally more tolerant to anticoagulants than male rats.
Conclusion: results suggest that bromadiolone resistance in a Danish strain of Norway rats involves enhanced anticoagulant metabolism catalysed by cytochrome P450-2e1, -3a2 and -3a3. This pharmacokinetically based bromadiolone resistance is to some extent sex differentiated, as female resistance furthermore seems to involve overexpression of cytochrome P450-2c13 and suppression of P450-2c12, whereas male resistance appears to involve P450-2a1 overexpression.
Original languageEnglish
JournalPest Management Science
Volume64
Issue number3
Pages (from-to)239-248
Number of pages10
ISSN1526-498X
DOIs
Publication statusPublished - 2008

    Research areas

  • Former LIFE faculty - Rattus norvegicus, anticoagulant resistance, bromadiolone, cytochrome P450, pharmacokinetics

ID: 8101864