近日,，科學(xué)家從來自全球四個(gè)洲的老鼠身上發(fā)現(xiàn)了一系列抗藥性基因突變情況，這18種基因突變都能讓老鼠能耐得住常見滅鼠藥的毒性,。
德國維爾茨堡大學(xué)的西蒙娜-羅斯特（Simone Rost）教授以及一個(gè)國際性研究小組近日對(duì)來自歐洲,、東亞、南非和美洲撒有抗凝血滅鼠劑（又名：華法令,，Warfarin）地區(qū)的超過250只老鼠進(jìn)行了研究,。在這些老鼠中,，研究人員一共發(fā)現(xiàn)了18種最新的抗藥型基因突變。該項(xiàng)研究報(bào)告近日刊登在了新一期《BMC遺傳學(xué)》（BMC Genetics）期刊上,。
羅斯特教授解釋道：“嚙齒動(dòng)物種群對(duì)于滅鼠藥之類的抗凝血化合物形成了抗體,，這已經(jīng)成為世界各地許多國家普遍存在的問題，也勢(shì)必會(huì)對(duì)滅害工作的效果帶來嚴(yán)重影響,。”
殺鼠靈是一種合成的雙香豆素類中效抗凝劑,，可抑制維生素K環(huán)氧化物還原酶（VKOR）的活性，干擾維生素K的循環(huán)轉(zhuǎn)化,，抑制凝血因子Ⅶ,、Ⅸ、Ⅹ,、Ⅱ的活化,，以達(dá)到防止血液凝固的目的。羅斯特和同事們一起對(duì)老鼠的VKORC1基因進(jìn)行研究,，這種基因是VKOR多蛋白復(fù)合體的一個(gè)關(guān)鍵成分,。據(jù)該研究論文的作者稱：“VKORC1基因發(fā)生突變可能會(huì)導(dǎo)致老鼠產(chǎn)生可遺傳性的抗藥性，其抗藥原理是：防止香豆素衍生物干擾還原酶的活性,。”
對(duì)于老鼠來說，產(chǎn)生了防止中毒流血而亡的抗藥基因突變也許保住了性命,，但研究人員表示,，它們需要付出的代價(jià)也并不小，因?yàn)檫@種基因突變同樣容易誘發(fā)動(dòng)脈鈣化,、骨質(zhì)疏松癥,、甚至阿爾茨海默病。因?yàn)榫S生素K除了能幫助血液正常凝固外,，還具有降低動(dòng)脈血管鈣離子沉積和將鈣“鎖”在骨頭“骨基質(zhì)”中的作用,。這也就是為什么研究人員在發(fā)生了基因突變的老鼠腎臟中測(cè)量到的鈣含量“高得驚人”。
生態(tài)學(xué)和進(jìn)化生物學(xué)助理教授科恩表示：“我們猜想這種基因突變有可能在我們對(duì)老鼠使用抗凝血滅鼠劑之前就已經(jīng)發(fā)生,，只是數(shù)量不多,。因?yàn)檫@類型的基因突變并不是良性突變——除了能幫助老鼠對(duì)抗抗凝血滅鼠劑的毒性外，對(duì)它們身體本身反而是有害的,。”（生物谷Bioon.com）
生物谷推薦原始出處：
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.
