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


CONCLUSIONS
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.
Markussen
Mette Dk
MD
Danish Pest Infestation Laboratory, Department of Integrated Pest Management, Faculty of Agricultural Sciences, University of Aarhus, Denmark.
Heiberg
Ann-Charlotte
AC
Fredholm
Merete
M
Kristensen
Michael
M
D015110:4-Hydroxycoumarins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000502:physiology; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics; D009154:Mutation; D051381:Rats; D012378:Rodenticides / Q000493:pharmacokinetics / Q000494:pharmacology*; D012737:Sex Factors; D012965:Sodium Chloride / Q000008:administration & dosage / Q000494:pharmacology; D064417:Vitamin K Epoxide Reductases
D015110:4-Hydroxycoumarins; D000925:Anticoagulants; D012378:Rodenticides; D012965:Sodium Chloride; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D064417:Vitamin K Epoxide Reductases; C021636:bromadiolone