K Dilger1, J Metzler, J C Bode, U Klotz. 1. Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Abstract
BACKGROUND/AIMS: In addition to the possible toxicological impact of cytochrome P4502E1 (CYP2E1) in alcohol-induced liver damage, its activity can be regarded as a variable for drug action in patients with alcoholic liver disease as CYP2E1 is involved in the metabolism of several drugs, for example, paracetamol and halogenated anesthetics. The purpose of our study was to acquire detailed knowledge of CYP2E1 activity in patients with progressingly severe manifestations of alcoholic liver disease. METHODS: The concentration ratio of 6-hydroxy-chlorzoxazone/chlorzoxazone in plasma 2 h after ingestion of 500 mg chlorzoxazone (so-called metabolic ratio) has been shown to reflect CYP2E1 activity in vivo. We examined CYP2E1 activity in 56 Caucasian inpatients with minor (n=20), more pronounced (n=14) and severe alcoholic liver disease (n=22). Alcohol abusers were compared to healthy teetotallers (n=14). RESULTS: Metabolic ratios were increased 3-fold in actively drinking (ethanol-induced) compared to abstaining (non-induced) patients with alcoholic liver disease (1.19+/-0.84 vs. 0.44+/-0.45, mean+/-SD, (p<0.0001). CYP2E1 activity was significantly lower in non-induced patients with severe alcoholic liver disease (0.19+/-0.10) than in healthy controls (0.50+/-0.28, p<0.01), abstaining alcohol abusers with minor (0.67+/-0.60, p<0.01) and more pronounced alcoholic liver disease (0.53+/-0.31, p<0.01). When non-induced patients with alcoholic liver disease were arranged in progressing order of liver damage (minor, more pronounced, severe alcoholic liver disease), there was a significant decline in CYP2E1 activity (p=0.0008). CONCLUSIONS: In non-induced patients, CYP2E1 activity decreases in line with severity of alcoholic liver disease. CYP2E1-mediated drug metabolism is significantly impaired in severe alcoholic liver disease.
BACKGROUND/AIMS: In addition to the possible toxicological impact of cytochrome P4502E1 (CYP2E1) in alcohol-induced liver damage, its activity can be regarded as a variable for drug action in patients with alcoholic liver disease as CYP2E1 is involved in the metabolism of several drugs, for example, paracetamol and halogenated anesthetics. The purpose of our study was to acquire detailed knowledge of CYP2E1 activity in patients with progressingly severe manifestations of alcoholic liver disease. METHODS: The concentration ratio of 6-hydroxy-chlorzoxazone/chlorzoxazone in plasma 2 h after ingestion of 500 mg chlorzoxazone (so-called metabolic ratio) has been shown to reflect CYP2E1 activity in vivo. We examined CYP2E1 activity in 56 Caucasian inpatients with minor (n=20), more pronounced (n=14) and severe alcoholic liver disease (n=22). Alcohol abusers were compared to healthy teetotallers (n=14). RESULTS: Metabolic ratios were increased 3-fold in actively drinking (ethanol-induced) compared to abstaining (non-induced) patients with alcoholic liver disease (1.19+/-0.84 vs. 0.44+/-0.45, mean+/-SD, (p<0.0001). CYP2E1 activity was significantly lower in non-induced patients with severe alcoholic liver disease (0.19+/-0.10) than in healthy controls (0.50+/-0.28, p<0.01), abstaining alcohol abusers with minor (0.67+/-0.60, p<0.01) and more pronounced alcoholic liver disease (0.53+/-0.31, p<0.01). When non-induced patients with alcoholic liver disease were arranged in progressing order of liver damage (minor, more pronounced, severe alcoholic liver disease), there was a significant decline in CYP2E1 activity (p=0.0008). CONCLUSIONS: In non-induced patients, CYP2E1 activity decreases in line with severity of alcoholic liver disease. CYP2E1-mediated drug metabolism is significantly impaired in severe alcoholic liver disease.
Authors: Elisa K McCarthy; Amanda Vakos; Merylin Cottagiri; Joel J Mantilla; Lakshmi Santhanam; David L Thomas; L Mario Amzel; Noel R Rose; Dolores B Njoku Journal: mSphere Date: 2018-10-10 Impact factor: 4.389