The expressions of ABCC4 and ABCG2 xenobiotic transporters in human keratinocytes are proliferation-related.

Department of Dermatology and Allergology, Faculty of Medicine, University of Szeged, Hungary.
Archives for Dermatological Research (Impact Factor: 2.71). 09/2011; 304(1):57-63. DOI: 10.1007/s00403-011-1174-4
Source: PubMed

ABSTRACT Xenobiotic transporters of the ATP-binding cassette (ABC) protein superfamily play important roles in maintaining the biochemical barrier of various tissues, but their precise functions in the skin are not yet known. Screening of the expressions of the known xenobiotic transporter genes in two in vitro keratinocyte differentiation models revealed that the ABCC4 and ABCG2 transporters are highly expressed in proliferating keratinocytes, their expressions decreasing along with differentiation. Abrogation of the ABCC4 and ABCG2 protein functions by siRNA-mediated silencing and chemical inhibition did not affect the proliferation of HaCaT cells. In contrast, disruption of the ABCG2 function had no effect on normal human epidermal keratinocyte proliferation, while the inhibition of ABCC-type transporters by probenecid resulted in a striking decrease in the proliferation of the cells. These results indicate that, besides their possible therapy-modulating effects, xenobiotic transporters may contribute significantly to other keratinocyte functions, such as cell proliferation.

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    ABSTRACT: The role of two ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in transdermal absorption of a typical common substrate was examined in vivo. Skin and plasma concentrations of rhodamine123 (Rho123) after dermal application were reduced in P-gp knockout (mdr1a/1b(-/-)) mice and were below the detection limit in P-gp and BCRP triple-knockout (mdr1a/1b/bcrp(-/-)) mice. Lower epidermal-to-hypodermal permeation of Rho123 in mdr1a/1b/bcrp(-/-) mouse skin compared to wild-type mouse skin was confirmed in an Ussing-type chamber experiment. The reduction in skin concentration after dermal application in mdr1a/1b/bcrp(-/-) mice was greater in dermis than in epidermis, suggesting functional expression of these transporters in two distinct skin compartments. Coadministration of the inhibitor itraconazole reduced the skin and plasma concentrations of Rho123 in wild-type mice, but not in mdr1a/1b/bcrp(-/-) mice, and a marked decrease of Rho123 concentration was seen in dermis, demonstrating that the functional activities of these transporters can be modulated in vivo. On the other hand, the distribution of Rho123 after intravenous infusion was higher in mdr1a/1b/bcrp(-/-) mice than in wild-type mice. This supports the occurrence of vectorial transport from skin into systemic circulation, and is consistent with the immunohistochemical localization of P-gp and BCRP in mouse dermal endothelial cells. BCRP was immunohistochemically identified in human epidermis and dermal endothelial cells. Thus, our findings show that ABC transporters in different compartments of skin contribute to transdermal absorption of a typical substrate in vivo and can be modulated by a specific inhibitor. These findings have implications for transdermal drug delivery.
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