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Clomethiazole inhibits cytochrome P450 2E1 and improves alcoholic liver disease
  1. Nicolas Hohmann1,
  2. Fabian Schröder2,
  3. Bernardo Moreira2,
  4. Haidong Teng2,
  5. Jürgen Burhenne1,
  6. Thomas Bruckner3,
  7. Sebastian Mueller2,
  8. Walter E Haefeli1,
  9. Helmut K Seitz4
  1. 1 Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University, Heidelberg, Germany
  2. 2 Department of Medicine, Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
  3. 3 Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
  4. 4 Krankenhaus Salem, Heidelberg, Baden-Württemberg, Germany
  1. Correspondence to Professor Helmut K Seitz, Krankenhaus Salem, 69121 Heidelberg, Germany; helmut_karl.seitz{at}urz.uni-heidelberg.de

https://doi.org/10.1136/gutjnl-2021-324727

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    In their article on recent advances in alcoholic liver disease (ALD), Avila and coworkers1 also mention the little-studied approach of inhibiting overexpressed cytochrome P450 2E1 (CYP2E1), which is induced by chronic ethanol consumption,2 causes generation of reactive oxidative species (ROS) and oxidative stress and stimulates hepatic steatosis and fibrosis.3 4 ROS also results in lipid peroxidation products such as 4-hydroxynonenal, which binds to DNA and generates highly carcinogenic etheno DNA adducts.4 In rodents, ALD can be partly prevented by CYP2E1 knock out5 or by administration of the strong noncompetitive CYP2E1 inhibitor clomethiazole.6 Conversely, ALD is enhanced in mice overexpressing CYP2E1,7 underlying the potential role of CYP2E1 activity in ALD.

    To study whether CYP2E1 inhibition also improves ALD in humans, we performed an open, randomised controlled clinical trial (EudraCT-Number 2012-005730-11, online supplemental materials 1–3), as approved by the responsible Ethics Committee of the Medical Faculty of Heidelberg University (AFmo-586/2014) (online supplemental material 4) and the German authorities (BfArM) in alcohol-dependent patients who were admitted to the hospital for alcohol detoxification therapy (ADT). After giving written informed consent (online supplemental material 5), ADT was performed either with clomethiazole …

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    Footnotes

    • WEH and HKS contributed equally.

    • Contributors The authors have contributed to this research as follows. NH: designed the protocol, organised and supervised the trial, analysed the data, wrote the manuscript. SM: supervision of the clinical part of the study. FS: collection and coordination of clinical data. BM: collection and coordination of clinical data. HT: collection and coordination of clinical data. JB: performed the chlorzoxazone measurements. TB: analysed the data. WEH: designed the protocol, analysed the data, wrote the manuscript. HKS: designed the protocol, analysed the data, wrote the manuscript, had access to all of the data and can vouch for the integrity of the data analyses.

    • Funding This research was funded in part by Heidelberger Volksbank eG.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.