Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps.
Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps.
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熟食诱变剂 2-氨基-1-甲基-6-苯基咪唑-[4,5-b]吡啶 (PhIP) 穿过人肠 Caco-2 细胞单层的运输：外排泵的作用。
DOI：
10.1093/carcin/20.11.2153
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发表时间：
1999
期刊：
影响因子：
4.7
通讯作者：
Walle,T
中科院分区：
文献类型：
--
作者：
Walle,UK;Walle,T
煎肉时形成的熟食诱变剂被认为是导致结肠癌、乳腺癌和前列腺癌的原因之一。这些诱变剂中最普遍的是2-amino-1-methyl-6-phenylimidazo[4，5-b]pyridine(PhIP)，它被吸收后被I相酶和II相酶激活。尽管现有数据表明PhIP在人体内被吸收，但吸收的程度和机制尚不清楚。在目前的研究中，我们研究了[~3H]PhIP通过人Caco-2肠上皮细胞单层的转运，这是一种被广泛接受的人体肠道吸收模型。根尖外流的表观渗透系数[表观渗透系数(PAPP)54.2±0.7×10-6 cm/S，均值±扫描电子显微镜，n=24]是根尖-基底外流的3.6倍(Papp15.1±0.6×10-6 cm/S，n=21，P<；0.0001)。平衡交换实验证明外流是一个真正的活性过程。用P-糖蛋白介导的转运抑制剂维拉帕米或多药耐药相关蛋白介导的转运抑制剂MK-571预先孵育，可刺激PhIP的内流和减少PhIP的外流，表明PhIP是这两种转运体的底物。在确定对熟食诱变剂的暴露时，应考虑这些发现。
Cooked-food mutagens formed when frying meat have been suggested to contribute to the etiology of colon, breast and prostate cancer. The most prevalent of these mutagens is 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which after absorption is bioactivated by both phase I and phase II enzymes. Although available data suggest absorption of PhIP in humans, the extent and mechanism of absorption are unknown. In the present study we examined the transport of [3H]PhIP through the human Caco-2 intestinal epithelial cell monolayer, a well-accepted model of human intestinal absorption. The influx, or absorption, was extensive and linear for 2 h and up to a PhIP concentration of 5 μM. Still, the basolateral to apical efflux [apparent permeability coefficient (Papp) 54.2 ± 0.7×10–6cm/s, mean ± SEM,n= 24] was 3.6 times greater than the apical to basolateral influx (Papp15.1 ± 0.6×10–6cm/s,n= 21,P< 0.0001). Equilibrium exchange experiments demonstrated the efflux to be a true active process. Preincubations with verapamil, an inhibitor of P-glycoprotein-mediated transport, or MK-571, an inhibitor of multidrug resistance-associated protein-mediated transport, stimulated influx and reduced efflux of PhIP, suggesting that PhIP is a substrate for both of these transporters. These findings should be considered when determining exposure to the cooked food mutagens.
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影响因子：
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