In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract.
In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract.
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DOI：
10.1111/bph.12576
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发表时间：
2014-04
影响因子：
7.3
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Fang ZZ;Krausz KW;Nagaoka K;Tanaka N;Gowda K;Amin SG;Perdew GH;Gonzalez FJ
GNF-351 是一种有效的芳烃受体 (AHR) 拮抗剂，可抑制二恶英反应元件依赖性和非依赖性活性。在此，研究了 GNF-351 的吸收、代谢和体内 AHR 拮抗剂活性。 LC-MS 代谢组学用于分析 GNF-351 体外和体内代谢。采用重组药物代谢酶来确定参与 GNF-351 代谢的酶。对 AHR 靶基因进行分析，以研究 GNF-351 对 AHR 激活的抑制作用。 GNF-351 与来自人或小鼠肝脏和肠道的微粒体一起孵育后，产生了多种 I 期代谢物，包括两种氧化型 GNF-351 和一种三去甲基化 GNF-351。肠道吸收不良导致小鼠血清（0-6小时）和尿液（24小时）中检测不到GNF-351水平，24小时后几乎所有GNF-351都在粪便中发现。粪便分析进一步揭示了所有体外 I 期代谢物。检测到新的代谢物，包括一种二氧化GNF-351、两种氧化三脱甲基GNF-351、一种氧化GNF-351的脱氢产物和一种二氧化GNF-351的硫酸化产物。细胞色素 P450 被证明是参与 GNF-351 代谢的主要酶。给小鼠口服后，GNF-351 很容易抑制 β-萘黄酮诱导的回肠和结肠中的 AHR 激活，但不能抑制肝脏中的 AHR 激活。虽然口服给药后吸收差和广泛代谢限制了纯AHR拮抗剂GNF-351在肝脏中的体内作用，但它可用于抑制肠和结肠中的AHR激活。
GNF-351 is a potent aryl hydrocarbon receptor (AHR) antagonist that inhibits dioxin response element-dependent and independent activities. Here, the absorption, metabolism and in vivo AHR antagonist activity of GNF-351 were investigated. LC-MS metabolomics was used to analyse GNF-351 metabolism in vitro and in vivo. Recombinant drug-metabolizing enzymes were employed to determine the enzymes involved in GNF-351 metabolism. Analysis of target AHR genes was performed to investigate the inhibitory effects of GNF-351 towards AHR activation. Several phase I metabolites were generated after GNF-351 was incubated with microsomes from human or mouse liver and intestine, including two oxidized GNF-351 and one tri-demethylated GNF-351. Poor absorption from the intestine resulted in no detectable levels of GNF-351 in mouse serum (0–6 h) and urine (24 h) and almost all GNF-351 was found in the faeces after 24 h. Analysis of faeces further revealed all the in vitro phase I metabolites. Novel metabolites were detected, including one di-oxidized GNF-351, two oxidized and tri-demethylated GNF-351, one dehydrogenated product of oxidized GNF-351, and one sulfation product of di-oxidized GNF-351. Cytochromes P450 were demonstrated to be the major enzymes involved in metabolism of GNF-351. After oral administration to mice, GNF-351 readily inhibited β-naphthoflavone-induced AHR activation in ileum and colon, but not that in the liver. While poor absorption and extensive metabolism after oral administration limited the in vivo effects of the pure AHR antagonist GNF-351 in liver, it could be used to inhibit AHR activation in intestine and colon.
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