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【 Nature Reviews Cancer编译】警惕药物和毒素通过乳
Transporter for milk toxins
来源
Nature Reviews Cancer AOP, published online 18 February 2005; doi:10.1038/nrc1576
作者
Helen Dell
原文
Many medicines, carcinogens and environmental contaminants accumulate in milk — a potential health risk for breast-fed infants and those fond of dairy food. Jonker and colleagues have identified the transporter responsible for the secretion of several drugs and toxins into milk in mice, cows and humans.
The authors were studying the breast cancer resistance protein ABCG2 (also known as BCRP), an ATP-binding cassette drug transporter. This transporter expels drugs, carcinogens and environmental toxins across the cell membrane, which can lead to multidrug resistance in cancer cells. Its substrates are many and varied, including the potent dietary mutagen PhIP (2-amino-1-methyl-6-phenylimidazol[4,5-b]pyridine); topotecan, a cancer drug; cimetidine, a common treatment for ulcers and heartburn; and acyclovir, an antiviral drug.
The presence of ABCG2 in the epithelia of the intestine, kidney and bile canal indicates that this transporter helps to limit toxins in the body, getting rid of them through several excretion routes. But Jonker and colleagues found the mouse ABCG2 protein at high levels in the mammary epithelia during pregnancy and lactation. By contrast, virgin or non-lactating mice had little ABCG2 in the mammary epithelia. There is a similar pattern in cows and humans, with ABCG2 being highly expressed in lactating mammary glands, but absent from non-lactating ones.
To test whether this transporter might be responsible for the secretion of toxic compounds into milk, the researchers injected lactating wild-type and Abcg2-null mice with PhIP or topotecan. In the wild-type mice, both compounds were concentrated into the milk, unlike the knockout mice, where there was no secretion of either compound. Moreover, giving the ABCG2 inhibitor GF120918 to the wild-type mice also blocked secretion of topotecan into their milk.
Why a transporter that usually has a protective role, eliminating harmful compounds from the body, also secretes toxins to a suckling infant is hard to understand. That the presence of ABCG2 in the mammary gland has been conserved from mice to cows and humans implies an important role, and the authors speculate that the transporter might also secrete nutrients into milk, compensating for the risk from toxin contamination. They note, however, that the suckling pups of Abcg2-null mothers did not seem to be malnourished.
The findings have several useful implications. ABCG2 substrates might well accumulate in milk and their use should probably be restricted for breast-feeding mothers, and possibly for dairy cattle. Conversely, there might be cases where the transfer of drugs through milk is desirable. For instance, acyclovir, an antiviral used to treat opportunistic viral infections in HIV-positive individuals, is also an ABCG2 substrate that is concentrated in milk, and using this delivery route might reduce transmission of viruses from mother to baby.
编译
很多药物，诱癌物质和环境污染物都蓄积在奶汁中，这对哺乳的婴儿和那些人们喜爱的日常食品来说，具有潜在的健康危险。Jonker和同事们已经确认这种运载体是鼠、牛和人中几种药物分泌物和毒素进入奶汁的原因。
作者正在研究乳腺癌抵抗蛋白ABCG2 (也称BCRP)——一个ATP结合盒药物运载体。这个运载体使药物、诱癌物质和环境毒素排出细胞膜，这可以导致癌细胞对多种药物的抵抗。它的底物很多且都不相同，包括食物疗法诱变剂PhIP（2-氨-1-甲基-6-苯基咪达唑仑[4,5-b]吡啶）；抗癌药托泊替康；西咪替丁；抗病毒药阿西洛韦。
ABCG2出现在肠、肾和胆小管上皮细胞表明这种运载体有助于限制毒素存在于身体中，通过几种分泌途径消除毒素。但Jonker和同事们发现鼠ABCG2蛋白在妊娠期和哺乳期的乳房上皮细胞中具有很高的浓度。与此相反，未交配或未哺乳的鼠乳房上皮细胞中只有少量ABCG2。牛和人中具有相似的情况。
为了测试这个运载体是否造成毒性化合物分泌进入奶汁，研究者用PhIP或托泊替康注射野生授乳或没有ABCG2的鼠。在野生型鼠中化合物都集中到了奶汁中，与敲除的鼠不同——它们的奶汁中没有任何化合物。而且，给与ABCG2抑制剂GF120918到野生型鼠中也阻止了托泊替康进入它们的奶汁。
为什么运载体通常具有保护作用，从身体消除有害化合物，但也分泌毒素进入哺乳的婴儿，这很难理解。从鼠到牛以及人，乳腺中的ABCG2都被保存下来，说明了一个重要的作用，并且作者猜测这个运载体可能也分泌营养素进入奶汁，来弥补毒素污染的危险。但是，他们特别指出ABCG2缺乏的母亲哺乳的幼仔好像并没有营养失调。
这个发现有几个重要的暗示。ABCG2底物可能适当蓄积在奶汁中，它们可能是对哺乳母亲的限制，尤其是奶牛。相反地，这种药物通过奶汁的转运在某种情形下也是需要的。例如，阿西洛韦在HIV阳性个体中通常用于治疗条件性病毒感染，但也浓集于奶汁中，这个传送途径减少了病毒从母亲到婴儿的传送。 [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-04-07 18:33
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