title: Genetic polymorphisms influencing xenobiotic metabolism and transport in patients with primary biliary cirrhosis.
abstract: Epidemiological data suggest that environmental factors may trigger autoimmunity 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 (cl/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.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kimura
authors.forename: Carlo
authors.initials: C
authors.lastname: Selmi
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: Tin K
authors.initials: TK
authors.lastname: Mao
authors.forename: Joseph
authors.initials: J
authors.lastname: Schauer
authors.forename: Mitchell
authors.initials: M
authors.lastname: Watnik
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Mikio
authors.initials: M
authors.lastname: Nishioka
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Pietro
authors.initials: P
authors.lastname: Invernizzi
authors.forename: Mauro
authors.initials: M
authors.lastname: Podda
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000368:Aged; D000483:Alleles; D001692:Biological Transport / Q000235:genetics; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D019450:Genes, MDR; D005838:Genotype; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D012720:Severity of Illness Index; D015262:Xenobiotics / Q000378:metabolism*
chemical_list: D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015262:Xenobiotics; D019392:Cytochrome P-450 CYP2E1; D019389:Cytochrome P-450 CYP2D6