Drug targeting CYP2E1 for the treatment of early-stage alcoholic steatohepatitis.
Alkanes
/ chemical synthesis
Animals
Cytochrome P-450 CYP2E1
/ chemistry
Cytochrome P-450 CYP2E1 Inhibitors
/ chemical synthesis
Fatty Liver, Alcoholic
/ drug therapy
Female
Hep G2 Cells
Humans
Lipoproteins, VLDL
/ blood
Liver
/ drug effects
Oxidative Stress
/ drug effects
Rats
Rats, Wistar
Reactive Oxygen Species
/ metabolism
Severity of Illness Index
Triglycerides
/ blood
Ursodeoxycholic Acid
/ analysis
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2020
2020
Historique:
received:
14
05
2020
accepted:
25
06
2020
entrez:
24
7
2020
pubmed:
24
7
2020
medline:
22
9
2020
Statut:
epublish
Résumé
Alcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH. In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies. A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol. Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.
Sections du résumé
BACKGROUND AND AIMS
Alcoholic steatohepatitis (ASH)-the inflammation of fatty liver-is caused by chronic alcohol consumption and represents one of the leading chronic liver diseases in Western Countries. ASH can lead to organ dysfunction or progress to hepatocellular carcinoma (HCC). Long-term alcohol abstinence reduces this probability and is the prerequisite for liver transplantation-the only effective therapy option at present. Elevated enzymatic activity of cytochrome P450 2E1 (CYP2E1) is known to be critically responsible for the development of ASH due to excessively high levels of reactive oxygen species (ROS) during metabolization of ethanol. Up to now, no rational drug discovery process was successfully initiated to target CYP2E1 for the treatment of ASH.
METHODS
In this study, we applied a rational drug design concept to develop drug candidates (NCE) including preclinical studies.
RESULTS
A new class of drug candidates was generated successfully. Two of the most promising small compounds named 12-Imidazolyl-1-dodecanol (abbr.: I-ol) and 1-Imidazolyldodecane (abbr.: I-an) were selected at the end of this process of drug discovery and developability. These new ω-imidazolyl-alkyl derivatives act as strong chimeric CYP2E1 inhibitors at a nanomolar range. They restore redox balance, reduce inflammation process as well as the fat content in the liver and rescue the physiological liver architecture of rats consuming continuously a high amount of alcohol.
CONCLUSIONS
Due to its oral application and therapeutic superiority over an off-label use of the hepatoprotector ursodeoxycholic acid (UDCA), this new class of inhibitors marks the first rational, pharmaceutical concept in long-term treatment of ASH.
Identifiants
pubmed: 32701948
doi: 10.1371/journal.pone.0235990
pii: PONE-D-20-13905
pmc: PMC7377376
doi:
Substances chimiques
Alkanes
0
Cytochrome P-450 CYP2E1 Inhibitors
0
Lipoproteins, VLDL
0
Reactive Oxygen Species
0
Triglycerides
0
n-dodecane
11A386X1QH
Ursodeoxycholic Acid
724L30Y2QR
Cytochrome P-450 CYP2E1
EC 1.14.13.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0235990Commentaires et corrections
Type : ErratumIn
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
World J Gastroenterol. 2014 Sep 28;20(36):12934-44
pubmed: 25278689
J Hepatol. 2012;56 Suppl 1:S39-45
pubmed: 22300464
J Lipid Res. 1999 Nov;40(11):1990-7
pubmed: 10553002
J Biol Chem. 1952 Mar;195(1):133-40
pubmed: 14938361
Am J Health Syst Pharm. 2014 Aug 1;71(15):1265-76
pubmed: 25027533
Bioorg Med Chem. 2005 Jun 2;13(12):4063-70
pubmed: 15911319
Arzneimittelforschung. 1987 May;37(5A):589-600
pubmed: 3619980
Gastroenterology. 2000 Dec;119(6):1637-48
pubmed: 11113085
Chem Res Toxicol. 1997 Oct;10(10):1205-12
pubmed: 9348445
J Clin Transl Hepatol. 2016 Sep 28;4(3):192-205
pubmed: 27777888
Arch Biochem Biophys. 1997 Jan 1;337(1):1-7
pubmed: 8990261
Adv Med Sci. 2006;51:54-9
pubmed: 17357278
Biochem Pharmacol. 1995 Nov 27;50(11):1775-82
pubmed: 8615855
World J Hepatol. 2016 Oct 8;8(28):1157-1168
pubmed: 27729952
PLoS One. 2014 Jun 30;9(6):e100059
pubmed: 24977709
Methods Enzymol. 1978;52:302-10
pubmed: 672633
Chem Biol Interact. 2004 Apr 15;147(3):331-40
pubmed: 15135088
J Gastrointestin Liver Dis. 2013 Jun;22(2):189-97
pubmed: 23799218
J Lipid Res. 2003 Nov;44(11):2193-201
pubmed: 12897184
Harvey Lect. 1965;59:49-87
pubmed: 5337823
N Engl J Med. 2009 Jun 25;360(26):2758-69
pubmed: 19553649
N Engl J Med. 2011 Nov 10;365(19):1781-9
pubmed: 22070475
Arch Toxicol. 2009 Jun;83(6):519-48
pubmed: 19448996
Scand J Gastroenterol. 2011 Oct;46(10):1257-66
pubmed: 21815863
Arch Biochem Biophys. 1959 May;82(1):70-7
pubmed: 13650640
Cochrane Database Syst Rev. 2008 Jul 16;(3):CD000551
pubmed: 18677775
Mol Cell Biochem. 2016 Oct;421(1-2):169-81
pubmed: 27544404
Annu Rev Biophys Biomol Struct. 2000;29:291-325
pubmed: 10940251
Hepatology. 2003 Apr;37(4):887-92
pubmed: 12668982
Cochrane Database Syst Rev. 2017 Mar 31;3:CD011646
pubmed: 28368093
Am J Transplant. 2013 Jan;13 Suppl 1:11-46
pubmed: 23237695
Pharmacol Ther. 2013 Apr;138(1):103-41
pubmed: 23333322
Int J Environ Res Public Health. 2010 May;7(5):1872-88
pubmed: 20622998
Alcohol Clin Exp Res. 1998 Oct;22(7):1538-43
pubmed: 9802540
Biomedicine. 1973 Jan 20;19(1):16-9
pubmed: 4351005
J Biol Chem. 2010 Jul 16;285(29):22282-90
pubmed: 20463018
Am J Gastroenterol. 2011 Sep;106(9):1638-45
pubmed: 21556038
Kidney Int. 2003 May;63(5):1687-96
pubmed: 12675844
Rev Recent Clin Trials. 2016;11(3):253-9
pubmed: 27527895
Drug Metab Rev. 1981;12(1):1-117
pubmed: 7028434
Hepatology. 2010 Jan;51(1):307-28
pubmed: 20034030
Methods Mol Biol. 2006;320:143-7
pubmed: 16719385
Arch Biochem Biophys. 2011 Mar 1;507(1):86-94
pubmed: 20727847
Biochem Biophys Res Commun. 1996 Feb 15;219(2):445-9
pubmed: 8605007
Ukr Biokhim Zh (1999). 2002 Jan-Feb;74(1):88-92
pubmed: 12199106
N Engl J Med. 2016 Dec 22;375(25):2501-2502
pubmed: 28002707
Free Radic Biol Med. 1994 Jan;16(1):73-97
pubmed: 8299999
Hepatology. 2008 May;47(5):1483-94
pubmed: 18393316
Indian J Clin Biochem. 2005 Jul;20(2):24-8
pubmed: 23105529
Postgrad Med J. 1997 Feb;73(856):75-80
pubmed: 9122101
Alcohol Res Health. 2003;27(3):247-56
pubmed: 15535453
Arch Biochem Biophys. 1996 Oct 1;334(1):59-66
pubmed: 8837739
J Hepatol. 2004 Oct;41(4):592-8
pubmed: 15464239
Autoimmun Rev. 2016 Sep;15(9):870-6
pubmed: 27393766
J Gastroenterol Hepatol. 2013 Aug;28 Suppl 1:77-84
pubmed: 23855300
Methods Enzymol. 1994;233:585-94
pubmed: 8015491
Clin Biochem. 1996 Jun;29(3):225-9
pubmed: 8740508
Am J Transplant. 2010 Jan;10(1):138-48
pubmed: 19951276
Hepatology. 2004 May;39(5):1390-7
pubmed: 15122768
Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002148
pubmed: 15846629
J Hepatol. 2001 Jul;35(1):134-46
pubmed: 11495032
World J Gastroenterol. 2016 Jan 7;22(1):8-23
pubmed: 26755857