近日,科学家从来自全球四个洲的老鼠身上发现了一系列抗药性基因突变情况,这18种基因突变都能让老鼠能耐得住常见灭鼠药的毒性。
德国维尔茨堡大学的西蒙娜-罗斯特(Simone Rost)教授以及一个国际性研究小组近日对来自欧洲、东亚、南非和美洲撒有抗凝血灭鼠剂(又名:华法令,Warfarin)地区的超过250只老鼠进行了研究。在这些老鼠中,研究人员一共发现了18种最新的抗药型基因突变。该项研究报告近日刊登在了新一期《BMC遗传学》(BMC Genetics)期刊上。
罗斯特教授解释道:“啮齿动物种群对于灭鼠药之类的抗凝血化合物形成了抗体,这已经成为世界各地许多国家普遍存在的问题,也势必会对灭害工作的效果带来严重影响。”
杀鼠灵是一种合成的双香豆素类中效抗凝剂,可抑制维生素K环氧化物还原酶(VKOR)的活性,干扰维生素K的循环转化,抑制凝血因子Ⅶ、Ⅸ、Ⅹ、Ⅱ的活化,以达到防止血液凝固的目的。罗斯特和同事们一起对老鼠的VKORC1基因进行研究,这种基因是VKOR多蛋白复合体的一个关键成分。据该研究论文的作者称:“VKORC1基因发生突变可能会导致老鼠产生可遗传性的抗药性,其抗药原理是:防止香豆素衍生物干扰还原酶的活性。”
对于老鼠来说,产生了防止中毒流血而亡的抗药基因突变也许保住了性命,但研究人员表示,它们需要付出的代价也并不小,因为这种基因突变同样容易诱发动脉钙化、骨质疏松症、甚至阿尔茨海默病。因为维生素K除了能帮助血液正常凝固外,还具有降低动脉血管钙离子沉积和将钙“锁”在骨头“骨基质”中的作用。这也就是为什么研究人员在发生了基因突变的老鼠肾脏中测量到的钙含量“高得惊人”。
生态学和进化生物学助理教授科恩表示:“我们猜想这种基因突变有可能在我们对老鼠使用抗凝血灭鼠剂之前就已经发生,只是数量不多。因为这类型的基因突变并不是良性突变——除了能帮助老鼠对抗抗凝血灭鼠剂的毒性外,对它们身体本身反而是有害的。”(生物谷Bioon.com)
生物谷推荐原始出处:
BMC Genetics 2009, 10:4doi:10.1186/1471-2156-10-4
Novel mutations in the VKORC1 gene of wild rats and mice – a response to 50 years of selection pressure by warfarin
Simone Rost1 , Hans-Joachim Pelz2 , Sandra Menzel1 , Alan D MacNicoll3 , Vanina León4 , Ki-Joon Song5 , Thomas J?kel6 , Johannes Oldenburg7 and Clemens R Müller1
1Department of Human Genetics, University of Wuerzburg, Wuerzburg, Germany
2Federal Research Centre for Cultivated Plants – Julius Kuehn-Institute, Vertebrate Research, Toppheideweg 88, 48161 Muenster, Germany
3Central Science Laboratory, Sand Hutton, York, UK
4Department of Ecology, Genetics and Evolution, Faculty of Exact and Natural Sciences, Buenos Aires University, Buenos Aires, Argentina
5Department of Microbiology, College of Medicine, Bank for Pathogenic viruses, Korea University, Seoul, Korea
6GTZ Office Bangkok, 193/63 Lake Ratchada Bldg., 16th Floor, New Ratchadapisek Road, Bangkok 10110, Thailand
7Institute of Experimental Haematology and Transfusion Medicine, University of Bonn, 53105 Bonn, Germany
Abstract
Background
Coumarin derivatives have been in world-wide use for rodent pest control for more than 50 years. Due to their retarded action as inhibitors of blood coagulation by repression of the vitamin K reductase (VKOR) activity, they are the rodenticides of choice against several species. Resistance to these compounds has been reported for rodent populations from many countries around the world and poses a considerable problem for efficacy of pest control.
Results
In the present study, we have sequenced the VKORC1 genes of more than 250 rats and mice trapped in anticoagulant-exposed areas from four continents, and identified 18 novel and five published missense mutations, as well as eight neutral sequence variants, in a total of 178 animals. Mutagenesis in VKORC1 cDNA constructs and their recombinant expression revealed that these mutations reduced VKOR activities as compared to the wild-type protein. However, the in vitro enzyme assay used was not suited to convincingly demonstrate the warfarin resistance of all mutant proteins
Conclusion
Our results corroborate the VKORC1 gene as the main target for spontaneous mutations conferring warfarin resistance. The mechanism(s) of how mutations in the VKORC1 gene mediate insensitivity to coumarins in vivo has still to be elucidated.