Differential expression of cytochrome P450 genes between bromadiolone-resistant and anticoagulant-susceptible Norway rats: a possible role for pharmacokinetics in bromadiolone resistance
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Differential expression of cytochrome P450 genes between bromadiolone-resistant and anticoagulant-susceptible Norway rats : a possible role for pharmacokinetics in bromadiolone resistance. / Markussen, Mette Drude Kjær; Heiberg, Ann-Charlotte; Fredholm, Merete; Kristensen, Michael.
I: Pest Management Science, Bind 64, Nr. 3, 2008, s. 239-248.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Differential expression of cytochrome P450 genes between bromadiolone-resistant and anticoagulant-susceptible Norway rats
T2 - a possible role for pharmacokinetics in bromadiolone resistance
AU - Markussen, Mette Drude Kjær
AU - Heiberg, Ann-Charlotte
AU - Fredholm, Merete
AU - Kristensen, Michael
PY - 2008
Y1 - 2008
N2 - 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.
AB - 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.
KW - Former LIFE faculty
KW - Rattus norvegicus
KW - anticoagulant resistance
KW - bromadiolone
KW - cytochrome P450
KW - pharmacokinetics
U2 - 10.1002/ps.1506
DO - 10.1002/ps.1506
M3 - Journal article
C2 - 18080289
VL - 64
SP - 239
EP - 248
JO - Pest Management Science
JF - Pest Management Science
SN - 1526-498X
IS - 3
ER -
ID: 8101864