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Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection
Author(s) -
Girardin F.,
Daali Y.,
GexFabry M.,
Rebsamen M.,
RouxLombard P.,
Cerny A.,
Bihl F.,
Binek J.,
Moradpour D.,
Negro F.,
Desmeules J.
Publication year - 2012
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/j.1365-2893.2011.01578.x
Subject(s) - hepatitis c virus , antibody , cyp2d6 , genotype , hepatitis c , virology , immunology , biology , medicine , virus , genetics , gene
Summary. 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.