Impact of regulatory polymorphisms in organic anion transporter genes in the human liver.
OBJECTIVE
The aim of this study was to evaluate whether genetic polymorphisms are responsible for individual variation in the expression levels of hepatic organic anion transporters.


METHODS
The mRNA levels of multidrug resistance-associated protein 2, organic anion transporting polypeptide (OATP) 1B1, OATP1B3 and OATP2B1 were determined by real-time polymerase chain reaction using liver tissue samples from 102 Japanese. The association between the mRNA levels of these transporters and the disappearance rate of indocyanine green was examined. The promoter region of each transporter gene was sequenced and the effects of single nucleotide polymorphisms (SNPs) in the promoter region [regulatory SNPs (rSNPs)] on mRNA levels were evaluated. Western blot analysis using hepatic crude plasma membrane was carried out to assess protein levels.


RESULTS
Expression levels of hepatic organic anion transporters vary considerably among individuals and possible links were observed between mRNA levels of these transporters and the disappearance rate of indocyanine green. In the OATP2B1 promoter region, we identified an rSNP (-282G > A) that significantly increased mRNA expression. Western blot analysis showed a remarkable increase in the OATP2B1 protein level in the homozygotes for the rSNP with a high mRNA level. In contrast, none of the rSNPs of multidrug resistance-associated protein 2, OATP1B1 and OATP1B3 affected the mRNA expression.


CONCLUSIONS
OATP2B1 -282G > A is a major factor affecting expression, suggesting a contribution to inter-individual differences in the expression level of OATP2B1.
Aoki
Masayo
M
Department of Pharmacy, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Terada
Tomohiro
T
Ogasawara
Ken
K
Katsura
Toshiya
T
Hatano
Etsuro
E
Ikai
Iwao
I
Inui
Ken-Ichi
K
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007564:Japan; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D027361:Organic Anion Transporters / Q000235:genetics* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism
D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; C450859:SLCO2B1 protein, human