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Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection

Cerny, A
Binek, J
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Published in Journal of viral hepatitis. 2012, vol. 19, no. 8, p. 568-73
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.
Keywords AdultAgedAutoantibodies/immunologyCohort StudiesCytochrome P-450 CYP2D6/genetics/metabolismDextromethorphan/metabolismDextrorphan/metabolismFemaleGenotypeHepatitis C, Chronic/pathologyHumansMaleMiddle AgedSwitzerland
PMID: 22762141
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Research groups Groupe Desmeules Jules (pharmacologie/toxicologie) (567)
Pharmaco-omiques et médecine de précision (1003)
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GIRARDIN, François et al. Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection. In: Journal of viral hepatitis, 2012, vol. 19, n° 8, p. 568-73. doi: 10.1111/j.1365-2893.2011.01578.x https://archive-ouverte.unige.ch/unige:26798

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Deposited on : 2013-03-13

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