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: F Girardin, Y Daali, M Gex-Fabry, M Rebsamen, P Roux-Lombard, A Cerny, F Bihl, J Binek, D Moradpour, F Negro, J Desmeules, Swiss Hepatitis C Cohort Study Group
• Journal: Journal of viral hepatitis (J Viral Hepat) Vol. 19 Issue 8 Pg. 568-73 (Aug 2012) ISSN: 1365-2893 [Electronic] England
• PMID: 22762141 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• Autoantibodies
• anti-liver kidney microsome antibody
• Dextrorphan
• Dextromethorphan
• Cytochrome P-450 CYP2D6

Topics

• Adult
• Aged
• Autoantibodies (immunology)
• Cohort Studies
• Cytochrome P-450 CYP2D6 (genetics, metabolism)
• Dextromethorphan (metabolism)
• Dextrorphan (metabolism)
• Female
• Genotype
• Hepatitis C, Chronic (pathology)
• Humans
• Male
• Middle Aged
• Switzerland