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

Girardin, François; Daali, Youssef; Gex-Fabry, Marianne; Rebsamen, Michela; Roux-Lombard, Pascale; Cerny, A; Bihl, Florian; Binek, J; Moradpour, D; Negro, Francesco; Desmeules, Jules Alexandre

doi:10.1111/j.1365-2893.2011.01578.x

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Title		Liver kidney microsomal type 1 antibodies reduce the CYP2D6 activity in patients with chronic hepatitis C virus infection
Authors		Girardin, François Daali, Youssef Gex-Fabry, Marianne Rebsamen, Michela Roux-Lombard, Pascale Cerny, A Bihl, Florian Binek, J Moradpour, D Negro, Francesco Desmeules, Jules Alexandre show all authors [1 - 11]
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		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
Identifiers		DOI: 10.1111/j.1365-2893.2011.01578.x PMID: 22762141
Full text		Article (Published version) (112 Kb) - Limited access to UNIGE
Structures		Faculté de médecine / Section de médecine clinique / Département de psychiatrie Faculté de médecine / Section de médecine clinique / Département de médecine Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie
Research groups		Groupe Desmeules Jules (pharmacologie/toxicologie) (567) Pharmaco-omiques et médecine de précision (1003)
Citation (ISO format)		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