Ethynylestradiol increases expression and activity of rat liver MRP3

Area of Science:

• Pharmacology
• Hepatology
• Drug Metabolism

Background:

• Multidrug resistance-associated proteins (Mrps) are crucial for xenobiotic and endobiotic transport.
• Ethinylestradiol (EE) is known to affect hepatic transporter expression.
• Understanding transporter dynamics is key to predicting drug disposition and toxicity.

Purpose of the Study:

• To investigate the impact of ethinylestradiol (EE) on the expression and function of Mrp3 and Mrp2 in rats.
• To elucidate the consequences of altered Mrp2 and Mrp3 expression on the biliary and sinusoidal excretion of acetaminophen glucuronide (APAP-glu).

Main Methods:

• Rats were administered EE (5 mg/kg s.c.) for 5 consecutive days.
• Western blotting was used to quantify Mrp2 and Mrp3 expression levels.
• The isolated perfused liver (IPL) model assessed APAP-glu excretion after APAP administration.

Main Results:

• EE administration significantly decreased Mrp2 expression (-41%) and increased Mrp3 expression (+200%).
• Biliary excretion of APAP-glu was reduced by 80% in EE-treated rats, while perfusate excretion increased by 45%.
• Liver APAP-glu content decreased by 36% in the EE group, with no change in total glucuronide amount.

Conclusions:

• EE-induced upregulation of Mrp3 promotes basolateral efflux of conjugated substrates at the expense of canalicular excretion via Mrp2.
• Induced Mrp3 expression may serve as a compensatory mechanism against intracellular accumulation of substrates when Mrp2 function is compromised.
• These findings highlight the complex interplay between hepatic transporters in response to xenobiotic exposure.