Gender-specific expression of liver organic anion transporters in rat.
BACKGROUND
Sex differences in drug pharmacokinetics have been well recognized and gender has been considered a risk factor for adverse events to medications. The aim of this study was to investigate the effect of gender on the expression of hepatocellular transport proteins involved in uptake and secretion of organic anions in rat.


METHODS
Expression of the rat liver organic anion transporting polypeptides (Oatps) and multidrug resistance proteins (Mrps) was analysed by reverse transcription polymerase chain reaction (RT-PCR), immunoblot analysis and immunofluorescence microscopy in male and female rats. Regulation of these transport proteins in response to the steroid dehydroepiandrosterone (DHEA) was investigated.


RESULTS
In untreated rats, protein expression significantly differed between genders being higher (Mrp2, Mrp3), comparable [Oatp1a1 (Oatp1); Oatp1b2 (Oatp4)] or lower [Oatp1a4 (Oatp2)] in female than in male rat. DHEA treatment over 3 days (100 mg d(-1)) led to a further increase in Mrp3 expression only in female rats. Mrp2 expression was not influenced by DHEA treatment. Oatp1a1 and Oatp1b2 were significantly down-regulated after DHEA treatment in both male and female rats. In contrast, Oatp1a4 was down-regulated in male rats only.


CONCLUSIONS
In rat, liver transport proteins of the Oatp and Mrp family are expressed and regulated in a gender-specific manner according to sexual differences in the hepatic metabolism of steroids and drugs. These findings may partly explain the well-known sex differences in hepatic handling of organic anions.
Rost
D
D
Department of Gastroenterology, University of Heidelberg, Germany. daniel.rost@med.uni-heidelberg.de
Kopplow
K
K
Gehrke
S
S
Mueller
S
S
Friess
H
H
Ittrich
C
C
Mayer
D
D
Stiehl
A
A
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D003687:Dehydroepiandrosterone / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting / Q000379:methods; D008099:Liver / Q000378:metabolism*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012269:Ribosomal Proteins / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D012727:Sex Characteristics
D018435:ATP Binding Cassette Transporter, Subfamily B; D003687:Dehydroepiandrosterone; D024101:Mitochondrial Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D029701:Saccharomyces cerevisiae Proteins; C093947:MRP2 protein, S cerevisiae; C114462:multidrug resistance-associated protein 3