TY - JOUR
T1 - Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis
AU - Kimura, Yasuhiko
AU - Selmi, Carlo
AU - Leung, Patrick S C
AU - Mao, Tin K.
AU - Schauer, Joseph
AU - Watnik, Mitchell
AU - Kuriyama, Shigeki
AU - Nishioka, Mikio
AU - Ansari, Aftab A.
AU - Coppel, Ross L.
AU - Invernizzi, Pietro
AU - Podda, Mauro
AU - Gershwin, M. Eric
PY - 2005/1
Y1 - 2005/1
N2 - Epidemiological data suggest that environmental factors may trigger autohnmunity in genetically susceptible individuals. In primary biliary cirrhosis (PBC), it has been postulated that halogenated xenobiotics can modify self-molecules, facilitating the breakdown of tolerance to mitochondrial antigens. The transport and metabolism of xenobiotics is highly dependent on key genetic polymorphisms that alter enzymatic phenotype. We analyzed genomic DNA from 169 patients with PBC and 225 geographically and sex-matched healthy subjects for polymorphisms of genes coding for cytochromes P450 (CYPs) 2D6 (CYP2D6*4, CYP2D6*3, CYP2D6*5, and CYP2D6*6) and 2E1 (c1/c2), multidrug resistance 1 (MDR1 C3435T) P-glycoprotein, and pregnane X receptor (PXR C-25385T, C8055T, and A7635G). We compared the genotype frequencies in patients and controls and also correlated polymorphisms with PBC severity. The distributions of the studied genotypes did not significantly differ between patients and controls. However, when clinical characteristics of patients with PBC were compared according to genotype, the CYP2E1 c2 allele was associated with signs of more severe disease. In conclusion, genetic polymorphisms of CYP 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of PBC.
AB - Epidemiological data suggest that environmental factors may trigger autohnmunity in genetically susceptible individuals. In primary biliary cirrhosis (PBC), it has been postulated that halogenated xenobiotics can modify self-molecules, facilitating the breakdown of tolerance to mitochondrial antigens. The transport and metabolism of xenobiotics is highly dependent on key genetic polymorphisms that alter enzymatic phenotype. We analyzed genomic DNA from 169 patients with PBC and 225 geographically and sex-matched healthy subjects for polymorphisms of genes coding for cytochromes P450 (CYPs) 2D6 (CYP2D6*4, CYP2D6*3, CYP2D6*5, and CYP2D6*6) and 2E1 (c1/c2), multidrug resistance 1 (MDR1 C3435T) P-glycoprotein, and pregnane X receptor (PXR C-25385T, C8055T, and A7635G). We compared the genotype frequencies in patients and controls and also correlated polymorphisms with PBC severity. The distributions of the studied genotypes did not significantly differ between patients and controls. However, when clinical characteristics of patients with PBC were compared according to genotype, the CYP2E1 c2 allele was associated with signs of more severe disease. In conclusion, genetic polymorphisms of CYP 2D6 and 2E1, PXR, and MDR1 do not appear to play a role in the onset of PBC.
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U2 - 10.1002/hep.20516
DO - 10.1002/hep.20516
M3 - Article
C2 - 15690482
AN - SCOPUS:19944427556
VL - 41
SP - 55
EP - 63
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 1
ER -