Pharmacogenetic analysis of adverse drug effect reveals genetic variant for susceptibility to liver toxicity.
A retrospective pharmacogenetic study was conducted to identify possible genetic susceptibility factors in patients in whom the administration of the anti-Parkinson drug, tolcapone (TASMAR), was associated with hepatic toxicity. We studied 135 cases of patients with elevated liver transaminase levels (ELT) of >/=1.5 times above the upper limit of normal, in comparison with matched controls that had also received the drug but had not experienced ELT. DNA samples were genotyped for 30 previously described or newly characterized bi-allelic single nucleotide polymorphisms (SNPs), representing 12 candidate genes selected based on the known metabolic pathways involved in the tolcapone elimination. SNPs located within the UDP-glucuronosyl transferase 1A gene complex, which codes for the enzymes involved in the main elimination pathway of the drug, were found to be significantly associated with the occurrence of tolcapone-associated ELTs.
Acuña
Gonzalo
G
F Hoffmann-La Roche Ltd, Basel, Switzerland. gonzalo.acuna@roche.com
Foernzler
Dorothee
D
Leong
Diane
D
Rabbia
Michael
M
Smit
Ralf
R
Dorflinger
Ernest
E
Gasser
Rodolfo
R
Hoh
Josephine
J
Ott
Jürg
J
Borroni
Edilio
E
To
Zung
Z
Thompson
Annick
A
Li
Jia
J
Hashimoto
Lara
L
Lindpaintner
Klaus
K
D001577:Benzophenones / Q000009:adverse effects* / Q000627:therapeutic use; D016001:Confidence Intervals; D005260:Female; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation / Q000235:genetics; D014453:Glucuronosyltransferase / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D009596:Nitrophenols; D016017:Odds Ratio; D010597:Pharmacogenetics / Q000379:methods* / Q000706:statistics & numerical data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D000077867:Tolcapone
D001577:Benzophenones; D009596:Nitrophenols; D000077867:Tolcapone; C110655:UDP-glucuronosyltransferase, UGT1A6; D014453:Glucuronosyltransferase