Ethynylestradiol increases expression and activity of rat liver MRP3.
We evaluated the effect of ethynylestradiol (EE) administration (5 mg/kg b.wt. s.c., for 5 consecutive days) on the expression and activity of multidrug resistance-associated protein 3 (Mrp3) in rats. Western blotting analysis revealed decreased Mrp2 (-41%) and increased Mrp3 (+200%) expression by EE. To determine the functional impact of up-regulation of Mrp3 versus Mrp2, we measured the excretion of acetaminophen glucuronide (APAP-glu), a common substrate for both transporters, into bile and perfusate in the recirculating isolated perfused liver (IPL) model. APAP-glu was generated endogenously from acetaminophen (APAP), which was administered as a tracer dose (2 micromol/ml) into the perfusate. Biliary excretion of APAP-glu after 60 min of perfusion was reduced in EE-treated rats (-80%). In contrast, excretion into the perfusate was increased by EE (+45%). Liver content of APAP-glu at the end of the experiment was reduced by 36% in the EE group. The total amount of glucuronide remained the same in both groups. Taken together, these results indicate that up-regulation of Mrp3 led to an exacerbated basolateral versus canalicular excretion of conjugated APAP in IPL. We conclude that induced expression of basolateral Mrp3 by EE may represent a compensatory mechanism to prevent intracellular accumulation of common Mrp substrates, either endogenous or exogenous, due to reduced expression and activity of apical Mrp2.
Ruiz
María L
ML
Instituto de Fisiología Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Argentina.
Villanueva
Silvina S M
SS
Luquita
Marcelo G
MG
Vore
Mary
M
Mottino
Aldo D
AD
Catania
Viviana A
VA
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000378:metabolism; D000082:Acetaminophen / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D000082:Acetaminophen; D004997:Ethinyl Estradiol; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C423013:Abcc2 protein, rat; C114462:multidrug resistance-associated protein 3; C037386:acetaminophen glucuronide