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口服后，纯芳烃受体拮抗剂GNF-351的体内效应仅限于胃肠道。

In vivo effects of the pure aryl hydrocarbon receptor antagonist GNF-351 after oral administration are limited to the gastrointestinal tract.

作者信息

Fang Zhong-Ze, Krausz Kristopher W, Nagaoka Kenjiro, Tanaka Naoki, Gowda Krishne, Amin Shantu G, Perdew Gary H, Gonzalez Frank J

机构信息

Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

出版信息

Br J Pharmacol. 2014 Apr;171(7):1735-46. doi: 10.1111/bph.12576.

DOI:10.1111/bph.12576
PMID:24417285
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3966752/
Abstract

BACKGROUND AND PURPOSE

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.

EXPERIMENTAL APPROACH

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.

KEY RESULTS

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.

CONCLUSION AND IMPLICATIONS

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.

摘要

背景与目的

GNF-351是一种有效的芳烃受体（AHR）拮抗剂，可抑制二噁英反应元件依赖性和非依赖性活性。在此，对GNF-351的吸收、代谢及体内AHR拮抗剂活性进行了研究。

实验方法

采用液相色谱-质谱代谢组学技术分析GNF-351在体外和体内的代谢情况。使用重组药物代谢酶来确定参与GNF-351代谢的酶。对靶标AHR基因进行分析，以研究GNF-351对AHR激活的抑制作用。

关键结果

GNF-351与人或小鼠肝脏及肠道微粒体孵育后产生了几种I相代谢产物，包括两种氧化型GNF-351和一种三去甲基化GNF-351。肠道吸收较差导致小鼠血清（0 - 6小时）和尿液（24小时）中未检测到GNF-351，24小时后几乎所有GNF-351都存在于粪便中。对粪便的分析进一步揭示了所有体外I相代谢产物。检测到了新的代谢产物，包括一种双氧化型GNF-351、两种氧化型和三去甲基化GNF-351、一种氧化型GNF-351的脱氢产物以及一种双氧化型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能有效抑制β-萘黄酮诱导的回肠和结肠中AHR的激活，但对肝脏中AHR的激活无抑制作用。

结论与意义

虽然口服后吸收较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，但它可用于抑制肠道和结肠中AHR的激活。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/c0e67e5dd280/bph0171-1735-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/1a5c019b3fa6/bph0171-1735-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/7cb36d02faf1/bph0171-1735-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/714ead4229ff/bph0171-1735-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/9605c2b80047/bph0171-1735-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/9c4dcafeb4e9/bph0171-1735-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/a1e16ff64e7e/bph0171-1735-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/4fea90b4a3bf/bph0171-1735-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/84dfcbeb0e1a/bph0171-1735-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/c0e67e5dd280/bph0171-1735-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/1a5c019b3fa6/bph0171-1735-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/7cb36d02faf1/bph0171-1735-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/714ead4229ff/bph0171-1735-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/9605c2b80047/bph0171-1735-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/9c4dcafeb4e9/bph0171-1735-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/a1e16ff64e7e/bph0171-1735-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/4fea90b4a3bf/bph0171-1735-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/84dfcbeb0e1a/bph0171-1735-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15c8/3966752/c0e67e5dd280/bph0171-1735-f9.jpg

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