The structure and characterization of human cytochrome P450 8B1 supports future drug design for nonalcoholic fatty liver disease and diabetes.

Abstract

Human cytochrome P450 8B1 (CYP8B1) is involved in conversion of cholesterol to bile acids. It hydroxylates the steroid ring at C12 to ultimately produce the bile acid cholic acid. Studies implicated this enzyme as a good drug target for nonalcoholic fatty liver disease and type 2 diabetes, but there are no selective inhibitors known for this enzyme and no structures to guide inhibitor development. Herein, the human CYP8B1 protein was generated and used to identify and characterize interactions with a series of azole inhibitors, which tend to be poorly selective P450 inhibitors. Structurally related miconazole, econazole, and tioconazole bound with submicromolar dissociation constants and were effective inhibitors of the native reaction. CYP8B was cocrystallized with S-tioconazole to yield the first X-ray structure. This inhibitor bound in the active site with its azole nitrogen coordinating the heme iron, consistent with inhibitor binding and inhibition assay data. Additionally, the CYP8B1 active site was compared with similar P450 enzymes to identify features that may facilitate the design of more selective inhibitors. Selective inhibitors should promote a better understanding of the role of CYP8B1 inhibition in normal physiology and disease states and provide a possible treatment for nonalcoholic fatty liver disease and type 2 diabetes.

• Authors: Jinghan Liu, Heather A Carlson, Emily E Scott
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 298 Issue 9 Pg. 102344 (09 2022) ISSN: 1083-351X [Electronic] United States
• PMID: 35944583 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Azoles
• Bile Acids and Salts
• Cholic Acids
• Heme
• Econazole
• Miconazole
• Cytochrome P-450 Enzyme System
• Cholesterol
• Iron
• Steroid 12-alpha-Hydroxylase
• Nitrogen

Topics

• Azoles (chemistry, pharmacology, therapeutic use)
• Bile Acids and Salts
• Cholesterol
• Cholic Acids
• Cytochrome P-450 Enzyme System (metabolism)
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Design
• Econazole (metabolism)
• Heme (metabolism)
• Humans
• Iron
• Miconazole
• Nitrogen
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Steroid 12-alpha-Hydroxylase (metabolism)