Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Department of Medical Biochemistry, Faculty of Medicine, Istinye University, Istanbul, Turkey.
Arch Toxicol. 2019 Mar;93(3):775-790. doi: 10.1007/s00204-019-02394-w. Epub 2019 Jan 30.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is an abundant dietary carcinogen, formed during high-temperature cooking of meat. In this study, we investigated whether clinically relevant ATP-binding cassette (ABC) efflux transporters can modulate PhIP-induced colorectal carcinogenesis in vivo using wild-type (WT), Bcrp1; Mrp2; Mrp3 and Bcrp1; Mdr1a/b; Mrp2 mice. We used a physiological mouse model of colorectal cancer; a combination of a single high-dose oral PhIP administration (200 mg/kg), followed by administering a colonic inflammatory agent, dextran sodium sulfate (DSS), in drinking water for 7 days. Pilot experiments showed that both knockout strains were more sensitive to DSS-induced colitis compared to WT mice. Lack of these transporters in mice also led to clearly altered disposition of activated PhIP metabolites after a high-dose oral PhIP administration. The results suggest that Mdr1a/1b, Bcrp1 and Mrp2 contributed to biliary excretion and Mrp3 to sinusoidal secretion of the pre-carcinogenic metabolite N2-OH-PhIP. The levels of a genotoxicity marker, PhIP-5-sulphate, were at least 4- and 17-fold reduced in the intestinal tissue and intestinal content of both knockout strains compared to WT mice. In line with these findings, the level of colon carcinogenesis was reduced by two- to four-fold in both knockout strains compared to WT mice when PhIP and DSS treatments were combined. Thus, perhaps counterintuitively, reduced activity of these ABC transporters may in part protect from PhIP-induced colon carcinogenesis. Collectively, these data suggest that ABC transporters are important in protecting the body from inflammatory agents such as DSS, in the disposition of carcinogenic metabolites, and in determining the sensitivity to dietary PhIP-induced carcinogenesis.
2-氨基-1-甲基-6-苯基咪唑并[4,5-b]吡啶（PhIP）是一种丰富的膳食致癌物质，在高温烹饪肉类时形成。在这项研究中，我们使用野生型（WT）、Bcrp1；Mrp2；Mrp3 和 Bcrp1；Mdr1a/b；Mrp2 小鼠，研究了临床上相关的三磷酸腺苷结合盒（ABC）外排转运体是否可以调节体内 PhIP 诱导的结直肠癌发生。我们使用了一种结直肠癌的生理小鼠模型；单次高剂量口服 PhIP 给药（200mg/kg）后，在饮用水中给予结肠炎症剂葡聚糖硫酸钠（DSS），持续 7 天。初步实验表明，与 WT 小鼠相比，两种敲除株对 DSS 诱导的结肠炎更为敏感。这些转运体在小鼠中的缺失也导致在口服高剂量 PhIP 给药后，活化的 PhIP 代谢物的处置明显改变。结果表明，Mdr1a/1b、Bcrp1 和 Mrp2 有助于前致癌代谢物 N2-OH-PhIP 的胆汁排泄，而 Mrp3 有助于其经窦状隙分泌。与 WT 小鼠相比，两种敲除株的肠道组织和肠道内容物中的遗传毒性标志物 PhIP-5-硫酸盐水平至少降低了 4 倍和 17 倍。与这些发现一致的是，当 PhIP 和 DSS 联合处理时，两种敲除株的结肠癌发生率比 WT 小鼠降低了 2 倍至 4 倍。因此，也许与直觉相反，这些 ABC 转运体的活性降低可能部分保护身体免受 PhIP 诱导的结肠癌发生。总的来说，这些数据表明，ABC 转运体在保护身体免受炎症剂（如 DSS）的影响、处置致癌代谢物以及确定对膳食 PhIP 诱导的致癌作用的敏感性方面具有重要作用。
