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. 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.     

洞庭湖区东方田鼠对溴敌隆的敏感性

从洞庭湖防洪大堤护坡和湖滩捕捉试鼠,在实验室做无选择性摄食试验。将试鼠雌雄分开,随机分组,配制0.000 2％溴敌隆毒饵进行不同时间的攻毒试验。用SPSS进行几率单位加权回归法(Bliss法)的计算,探讨不同食毒期与对应死亡率之间的关系。结果表明,东方田鼠性别之间对溴敌隆的敏感性差异无统计学意义,故将雌雄数据合并计算,得毒力回归方程y=0.07+2.65x,LFP50、LFP98、LFP99及其95％置信限分别是0.94(0.43～1.33)、5.63(3.51～20.83) d和7.14(4.15～33.52) d。按WHO修订以致死99％敏感靶标鼠种的食毒期(LFP99)取整天数作为抗药性检验标准,洞庭湖区东方田鼠对0.000 2％的溴敌隆毒饵食毒期超过8 d存活为产生抗药性。