title: Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection.
abstract: Liver kidney microsomal type 1 (LKM-1) antibodies have been shown to decrease the CYP2D6 activity in vitro and are present in a minority of patients with chronic hepatitis C infection. We investigated whether LKM-1 antibodies might reduce the CYP2D6 activity in vivo. All patients enrolled in the Swiss Hepatitis C Cohort Study and tested for LKM-1 antibodies were assessed (n = 1723): 10 eligible patients were matched with patients without LKM-1 antibodies. Patients were genotyped for CYP2D6 variants to exclude individuals with a poor metabolizer genotype. CYP2D6 activity was measured by a specific substrate using the dextromethorphan/dextrorphan metabolic ratio to classify patients into four activity phenotypes. All patients had a CYP2D6 extensive metabolizer genotype. The observed phenotype was concordant with the CYP2D6 genotype in most LKM-negative patients, whereas only three LKM-1 positive patients had a concordant phenotype (six presented an intermediate and one a poor metabolizer phenotype). The median DEM/DOR ratio was sixfold higher in LKM-1 positive than in LKM-1 negative patients (0.096 vs. 0.016, P = 0.004), indicating that CYP2D6 metabolic function was significantly reduced in the presence of LKM-1 antibodies. In chronic hepatitis C patients with LKM-1 antibodies, the CYP2D6 metabolic activity was on average reduced by 80%. The impact of LKM-1 antibodies on CYP2D6-mediated drug metabolism pathways warrants further translational studies.
authors: Division of Clinical Pharmacology and Toxicology, University of Geneva, University Hospitals of Geneva, Switzerland. francois.girardin@hcuge.ch
authors: F
authors: F
authors: Girardin
authors: Y
authors: Y
authors: Daali
authors: M
authors: M
authors: Gex-Fabry
authors: M
authors: M
authors: Rebsamen
authors: P
authors: P
authors: Roux-Lombard
authors: A
authors: A
authors: Cerny
authors: F
authors: F
authors: Bihl
authors: J
authors: J
authors: Binek
authors: D
authors: D
authors: Moradpour
authors: F
authors: F
authors: Negro
authors: J
authors: J
authors: Desmeules
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000378:metabolism; D003917:Dextrorphan / Q000378:metabolism; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013557:Switzerland
chemical_list: D001323:Autoantibodies; C060729:anti-liver kidney microsome antibody; D003917:Dextrorphan; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6