A synthesis of a rationally designed inhibitor of cytochrome P450 8B1, a therapeutic target to treat obesity.
A synthesis of a rationally designed inhibitor of cytochrome P450 8B1, a therapeutic target to treat obesity.
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DOI：
10.1016/j.steroids.2021.108952
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发表时间：
2022-03
期刊：
影响因子：
2.7
通讯作者：
Yoshimoto FK
中科院分区：
文献类型：
--
作者：
Chung E;Offei SD;Aondo Jia UT;Estevez J;Perez Y;Arman HD;Yoshimoto FK
缺乏细胞色素P450 8B 1（P450 8B 1）表达基因的小鼠在喂食高脂肪饮食时抵抗体重增加并改善葡萄糖耐量。因此，抑制P450 8B 1是治疗肥胖相关代谢紊乱的靶点。P450 8B 1是将其底物7α-羟基-胆甾-4-烯-3-酮羟基化为7α-，12 α-二羟基胆甾-4-烯-3-酮的酶，最终导致胆酸的形成。胆酸是与胆固醇吸收增强有关的12α-羟基化胆汁酸。通过在甾体分子的C环中引入C12-吡啶，实现了合理设计的P450 8B 1抑制剂的合成。7天的新抑制剂治疗显示，在喂食高脂肪和高蔗糖饮食（HFHS）的小鼠中，葡萄糖耐受不良减轻，而不影响体重。总之，这些有希望的结果将导致P450 8B 1抑制剂作为治疗肥胖相关胰岛素抵抗的潜在治疗策略。
Mice that lack the gene for expression of cytochrome P450 8B1 (P450 8B1) resist weight gain and improve glucose tolerance when fed a high-fat diet. Thus, the inhibition of P450 8B1 is a target to treat obesity-associated metabolic disorders. P450 8B1 is the enzyme that hydroxylates its substrate, 7α-hydroxy-cholest-4-en-3-one to 7α-,12α-dihydroxycholest-4-en-3-one, which ultimately results in the formation of cholic acid. Cholic acid is the 12α-hydroxylated bile acid implicated in enhanced absorption of cholesterol. The synthesis of a rationally designed inhibitor for P450 8B1 was achieved through the incorporation of a C12-pyridine in the C-ring of a steroid molecule. Seven days of new inhibitor treatment showed attenuation of glucose intolerance in mice that were fed a high fat and a high sucrose diet (HFHS) without affecting body weight. Taken together, these promising results will lead to a P450 8B1 inhibitor as a potential therapeutic strategy to treat obesity-associated insulin resistance.
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