Characterization of ABC transporters in human skin.

BACKGROUND: Most identified drug transporters belong to the ATP-binding cassette (ABC) and solute carrier (SLC) families. Recent research indicates that these transporters play an important role in the absorption, distribution and excretion of drugs, and are involved in clinically relevant drug-drug interactions for systemic drugs. However, very little is known about the role of drug transporters in human skin, especially in the disposition of topically applied drugs, and their involvement in drug-drug interactions. The aim of this work was to characterize the ABC transporters in human skin.

METHODS: Expressions of ABCB1 multidrug resistance protein 1 (MDR1) also known as P-gp, ABCC1 and ABCC2 multidrug resistance-associated protein 1 and 2 (MRP1 and MRP2), and ABCG2 brest cancer resistance protein (BCRP) in human skin tissues were analyzed by quantitative real-time polymerase chain reaction (RT-PCR). The modulations of ABCB1 and ABCC1 expressions were analyzed after ex vivo treatment of human skin with rifampicin and dexamethasone. The localization of the major transporter MRP1 in human skin was analyzed by immunohistochemistry. Finally, functional analysis of MRP1 in human skin was performed using different specific substrates and inhibitors.

RESULTS: The expressions of ABCB1, ABCC1, ABCC2, and ABCG2 were all detected in human skin, of which the expression of ABCC1 was considered the most important. The comparison of human skin with human hepatocytes and kidneys shows that the expression of ABCC1 increased 15-fold in skin than in hepatocytes. Immunohistochemistry revealed marked expressions of MRP1 within the hair follicle, sweat gland and muscle, as well as moderate expression in the basal epidermis. Functional analysis demonstrated that the skin absorptions of rhodamine 123, [3H]-vinblastine, and [3H]-LTC4 were markedly decreased in the presence of MRP1 inhibitors (verapamil and MK571), thus supporting the role of MRP1 in the uptake of compounds from the epidermal compartment as well as their secretion into the bloodstream and sweat ducts.

CONCLUSIONS: The present findings are the first to demonstrate the involvement of MRP1 in drug uptake in human skin.