Open Accessω‐Imidazolyl‐alkyl derivatives as new preclinical drug candidates for treating non‐alcoholic steatohepatitis
Author(s) -
Diesinger Torsten,
Lautwein Alfred,
Buko Vyacheslav,
Belonovskaya Elena,
Lukivskaya Oksana,
Naruta Elena,
Kirko Siarhei,
Andreev Viktor,
Dvorsky Radovan,
Buckert Dominik,
Bergler Sebastian,
Renz Christian,
MüllerEnoch Dieter,
Wirth Thomas,
Haehner Thomas
Publication year - 2021
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.14795
Subject(s) - cyp2e1 , steatohepatitis , ursodeoxycholic acid , alcoholic liver disease , pharmacology , medicine , fatty liver , tolerability , chemistry , drug , endocrinology , biochemistry , cytochrome p450 , cirrhosis , metabolism , disease , adverse effect
Cytochrome P450 2E1 (CYP2E1)‐associated reactive oxygen species production plays an important role in the development and progression of inflammatory liver diseases such as alcoholic steatohepatitis. We developed two new inhibitors for this isoenzyme, namely 12‐imidazolyl‐1‐dodecanol (I‐ol) and 1‐imidazolyldodecane (I‐an), and aimed to test their effects on non‐alcoholic steatohepatitis (NASH). The fat‐rich and CYP2E1 inducing Lieber‐DeCarli diet was administered over 16 weeks of the experimental period to induce the disease in a rat model, and the experimental substances were administered simultaneously over the last four weeks. The high‐fat diet (HFD) pathologically altered the balance of reactive oxygen species and raised the activities of the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and γ‐glutamyl‐transferase (γ‐GT); lowered the level of adiponectine and raised the one of tumor necrosis factor (TNF)‐α; increased the hepatic triglyceride and phospholipid content and diminished the serum HDL cholesterol concentration. Together with the histological findings, we concluded that the diet led to the development of NASH. I‐ol and, to a lesser extent, I‐an shifted the pathological values toward the normal range, despite the continued administration of the noxious agent (HFD). The hepatoprotective drug ursodeoxycholic acid (UDCA), which is used off‐label in clinical practice, showed a lower effectiveness overall. I‐ol, in particular, showed extremely good tolerability during the acute toxicity study in rats. Therefore, cytochrome P450 2E1 may be considered a suitable drug target, with I‐ol and I‐an being promising drug candidates for the treatment of NASH.