Clomethiazole inhibits cytochrome P450 2E1 and improves alcoholic liver disease
Nicolas Hohmann, Fabian Schröder, Bernardo Pereira Moreira, Haidong Teng, Jürgen Burhenne, Thomas Brückner, Sebastian Mueller, Walter E. Haefeli, Helmut K. Seitz
Abstract
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 …