Challenges in Discovering Selective CYP8B1 Inhibitor: Case Studies of Natural Triterpenoids and Bile Acids

Challenges in Discovering Selective CYP8B1 Inhibitor: Case Studies of Natural Triterpenoids and Bile Acids | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL British Journal of Pharmacology This is a preprint and has not been peer reviewed. Data may be preliminary. 12 May 2026 V1 Latest version Share on Challenges in Discovering Selective CYP8B1 Inhibitor: Case Studies of Natural Triterpenoids and Bile Acids Authors : Yixuan Wang [email protected] , Yutong Wang [email protected] , Xinjie Zhang [email protected] , Tingting Yu [email protected] , Lanlan Gui [email protected] , Wushuang Zeng [email protected] , Hengyi Zhu [email protected] , Boping Wei [email protected] , Liang Huang [email protected] , and K Lan [email protected] Authors Info & Affiliations https://doi.org/10.22541/authorea.15003050/v1 19 views 20 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract This study investigates the multiscale challenges in discovering sterol 12α-hydroxylase (CYP8B1) inhibitors by integrated enzymatic assays, cellular flux analysis, and species-adapted in vivo profiling, using natural triterpenoids and bile acids as a case study. A dual-probe screening platform combining 12α-hydroxylation assays of 7α-hydroxy-4-cholesten-3-one (C4) and dihydroxycoprostanic acid (DHCA) was established to mitigate substrate bias in evaluating inhibitory efficacy in recombinant and microsomal systems. Econazole was identified as a potent CYP8B1 inhibitor with selectivity over cholesterol 7α-hydroxylase (CYP7A1). Screening of 70 natural products revealed moderate dual CYP8B1/7A1 inhibition by oleanolic acid, oleanonic acid, and 20S-protopanaxadiol. Metabolic flux analysis of bile acid biosynthesis in HepG2 cells confirmed their dual inhibition and suggested additional off-target effects on oxysterol 7α-hydroxylase (CYP7B1), particularly for oleanonic acid. In vivo studies in bile duct-cannulated rats revealed cholestatic risks for all compounds following intraperitoneal administration. Econazole emerged as the first CYP8B1 inhibitor with dose-dependent in vivo activity. While oleanolic acid and 20S-protopanaxadiol showed weaker dose-dependent effects, oleanonic acid paradoxically increased 12α-hydroxylation despite potent in vitro activity, underscoring the profound structural sensitivity of steroid-like scaffolds. Although selective natural CYP8B1 inhibitors were not identified, this work establishes key methodological and pharmacological insights for future drug discovery efforts targeting CYP8B1. Information & Authors Information Version history V1 Version 1 12 May 2026 Collection British Journal of Pharmacology Authors Affiliations Yixuan Wang [email protected] View all articles by this author Yutong Wang [email protected] Sichuan University West China School of Pharmacy, Chengdu, China, 610041 View all articles by this author Xinjie Zhang [email protected] Sichuan University West China School of Pharmacy, Chengdu, China, 610041 View all articles by this author Tingting Yu [email protected] Sichuan University West China School of Pharmacy, Chengdu, China, 610041 View all articles by this author Lanlan Gui [email protected] View all articles by this author Wushuang Zeng [email protected] View all articles by this author Hengyi Zhu [email protected] View all articles by this author Boping Wei [email protected] Sichuan University West China School of Pharmacy, Chengdu, China, 610041 View all articles by this author Liang Huang [email protected] View all articles by this author K Lan [email protected] View all articles by this author Metrics & Citations Metrics Article Usage 19 views 20 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Yixuan Wang, Yutong Wang, Xinjie Zhang, et al. Challenges in Discovering Selective CYP8B1 Inhibitor: Case Studies of Natural Triterpenoids and Bile Acids. Authorea . 12 May 2026. DOI: https://doi.org/10.22541/authorea.15003050/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu . 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