ABCB1 polymorphism is associated with atorvastatin-induced liver injury in Japanese population.
To investigate the associations between atorvastatin-induced liver injury (AILI) and polymorphisms in eight genes possibly involved in the hepatic metabolism (CYP2C9, CYP2C19, CYP3A4, CYP3A5 and UGT1A1) and membrane transport (ABCB1, ABCG2 and SLCO1B1) of atorvastatin, we genotyped 30 AILI and 414 non-AILI patients recruited at BioBank Japan for 15 single nucleotide polymorphisms (SNPs).



An SNP in ABCB1 (rs2032582: 2677G > T/A) was significantly associated with AILI (P = 0.00068, odds ratio (OR) = 2.59 with 95 % confidence interval (CI) of 1.49-4.50, G allele versus T and A alleles), indicating that the G allele might be a risk factor for AILI. The cytotoxicity test demonstrated that IC50 value of atorvastatin to inhibit the growth and/or viability of Flp-In-293/ABCB1 (2677G) cells was 5.44 ± 0.10 mM, which was significantly lower than those in Flp-In-293/ABCB1 (2677 T) (6.02 ± 0.07 mM) and Flp-In-293/ABCB1 (2677A) cells (5.95 ± 0.08 mM).



These results indicate that ABCB1 rs2032582 may predict the risk of AILI in Japanese population.
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Koya
K
Fukunaga
Department of Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, Aichi, Japan.
Hiroshi
H
Nakagawa
NPO Personalized Medicine & Healthcare, Yokohama, Japan.
Toshihisa
T
Ishikawa
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Michiaki
M
Kubo
Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. mushiroda@riken.jp.
Taisei
T
Mushiroda
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D044466:Asian People / Q000235:genetics*; D000069059:Atorvastatin / Q000009:adverse effects*; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007564:Japan; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000069059:Atorvastatin
Atorvastatin-induced adverse reaction; Genetic association; Hepatotoxicity; MDR1 Ala893Ser/Thr/