Expression of drug transporters in the human skin: comparison in different species and models and its implication for drug development

It is clear that many drug transporters (both ABCs and SLCs) are present in the human skin. Different in vitro skin models can be used to investigate the role of drug transporters in the skin despite quantitative differences in expression profile across species. P-gp was shown to have an important influence on transdermal drug absorption in the skin and to function in “absorptive” transport, carrying substrate drugs from the skin surface to the dermis. This observation might be used to modulate drug distribution inside the skin. If drugs can be retained in the epidermis compartment by inhibition of the transporters, such property of the drug would be beneficial for treatment of dermatological diseases. Therefore, it might be feasible to control transdermal delivery of drugs to specific locations in the skin, by modulating the function of the transporters in the skin. We are at the dawn of an exciting period where drug transporters might be novel targets for improvement of drug delivery to the skin and for pharmacological intervention

Characterization of SLC transporters in human skin

Most identified drug transporters belong to the ATP-binding Cassette (ABC) and Solute Carrier (SLC) families. Recent research indicates that some of 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 in the disposition of topically applied drugs and their involvement in drug-drug interactions. The aim of this work was to compare the expression in human skin (vs human hepatocytes and kidney) of SLC transporters included in the EMA guidance as the most likely clinical sources of drug interactions. The expression of SLC transporters in human tissues was analyzed by quantitative RT-PCR. Modulation of SLC47A1 and SLC47A2 (MATE1 and MATE2) expression was analyzed after treatment of human skin in organ-culture with rifampicin and UV irradiation. The expression of SLCO2B1 (OATPB), SLCO3A1 (OATPD), SLCO4A1 (OATPE), SLC47A1 and SLC47A2 (MATE1 and MATE2) was detected in human skin, OATPE and MATE1 being the most expressed. OATPE is about 70 times more expressed in human skin than in human hepatocytes. Moreover, the expression of SLC47A1 and SLC47A2 was down-regulated after treatment with rifampicin or after exposure to UV light. The present findings demonstrate that SLCO4A1 (OATPE) and SLC47A1 (MATE1) are highly expressed in human skin and suggest the involvement of SLC transporters in the disposition of topically applied drugs

Receptors and Cofactors That Contribute to SARS-CoV-2 Entry: Can Skin Be an Alternative Route of Entry?

To prevent the spread of SARS-CoV-2, all routes of entry of the virus into the host must be mapped. The skin is in contact with the external environment and thus may be an alternative route of entry to transmission via the upper respiratory tract. SARS-CoV-2 cell entry is primarily dependent on ACE2 and the proteases TMPRSS2 or cathepsin L but other cofactors and attachment receptors have been identified that may play a more important role in specific tissues such as the skin. The continued emergence of new variants may also alter the tropism of the virus. In this review, we summarize current knowledge on these receptors and cofactors, their expression profile, factors modulating their expression and their role in facilitating SARS-CoV-2 infection. We discuss their expression in the skin and their possible involvement in percutaneous infection since the presence of the virus has been detected in the skin

Characterization of SLC transporters in human skin

Most identified drug transporters belong to the ATP-binding Cassette (ABC) and Solute Carrier (SLC) families. Recent research indicates that some of 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 in the disposition of topically applied drugs and their involvement in drug-drug interactions. The aim of this work was to compare the expression in human skin (vs human hepatocytes and kidney) of SLC transporters included in the EMA guidance as the most likely clinical sources of drug interactions. The expression of SLC transporters in human tissues was analyzed by quantitative RT-PCR. Modulation of SLC47A1 and SLC47A2 (MATE1 and MATE2) expression was analyzed after treatment of human skin in organ-culture with rifampicin and UV irradiation. The expression of SLCO2B1 (OATPB), SLCO3A1 (OATPD), SLCO4A1 (OATPE), SLC47A1 and SLC47A2 (MATE1 and MATE2) was detected in human skin, OATPE and MATE1 being the most expressed. OATPE is about 70 times more expressed in human skin than in human hepatocytes. Moreover, the expression of SLC47A1 and SLC47A2 was down-regulated after treatment with rifampicin or after exposure to UV light. The present findings demonstrate that SLCO4A1 (OATPE) and SLC47A1 (MATE1) are highly expressed in human skin and suggest the involvement of SLC transporters in the disposition of topically applied drugs

Membrane transporter data to support kinetically-informed chemical risk assessment using non-animal methods: Scientific and regulatory perspectives

Humans are continuously exposed to low levels of thousands of industrial chemicals, most of which are poorly characterised in terms of their potential toxicity. The new paradigm in chemical risk assessment (CRA) aims to rely on animal-free testing, with kinetics being a key determinant of toxicity when moving from traditional animal studies to integrated in vitro-in silico approaches. In a kinetically informed CRA, membrane transporters, which have been intensively studied during drug development, are an essential piece of information. However, how existing knowledge on transporters gained in the drug field can be applied to CRA is not yet fully understood. This review outlines the opportunities, challenges and existing tools for investigating chemical-transporter interactions in kinetically informed CRA without animal studies. Various environmental chemicals acting as substrates, inhibitors or modulators of transporter activity or expression have been shown to impact TK, just as drugs do. However, because pollutant concentrations are often lower in humans than drugs and because exposure levels and internal chemical doses are not usually known in contrast to drugs, new approaches are required to translate transporter data and reasoning from the drug sector to CRA. Here, the generation of in vitro chemical-transporter interaction data and the development of transporter databases and classification systems trained on chemical datasets (and not only drugs) are proposed. Furtheremore, improving the use of human biomonitoring data to evaluate the in vitro-in silico transporter-related predicted values and developing means to assess uncertainties could also lead to increase confidence of scientists and regulators in animal-free CRA. Finally, a systematic characterisation of the transportome (quantitative monitoring of transporter abundance, activity and maintenance over time) would reinforce confidence in the use of experimental transporter/barrier systems as well as in established cell-based toxicological assays currently used for CRA.JRC.F.3-Chemicals Safety and Alternative Method

Membrane transporter data to support kinetically-informed chemical risk assessment using non-animal methods Scientific and regulatory perspectives

International audienceHumans are continuously exposed to low levels of thousands of industrial chemicals, most of which are poorly characterised in terms of their potential toxicity. The new paradigm in chemical risk assessment (CRA) aims to rely on animal-free testing, with kinetics being a key determinant of toxicity when moving from traditional animal studies to integrated in vitro-in silico approaches. In a kinetically informed CRA, membrane transporters, which have been intensively studied during drug development, are an essential piece of information. However, how existing knowledge on transporters gained in the drug field can be applied to CRA is not yet fully understood. This review outlines the opportunities, challenges and existing tools for investigating chemical-transporter interactions in kinetically informed CRA without animal studies. Various environmental chemicals acting as substrates, inhibitors or modulators of transporter activity or expression have been shown to impact TK, just as drugs do. However, because pollutant concentrations are often lower in humans than drugs and because exposure levels and internal chemical doses are not usually known in contrast to drugs, new approaches are required to translate transporter data and reasoning from the drug sector to CRA. Here, the generation of in vitro chemical-transporter interaction data and the development of transporter databases and classification systems trained on chemical datasets (and not only drugs) are proposed. Furtheremore, improving the use of human biomonitoring data to evaluate the in vitro-in silico transporter-related predicted values and developing means to assess uncertainties could also lead to increase confidence of scientists and regulators in animal-free CRA. Finally, a systematic characterisation of the transportome (quantitative monitoring of transporter abundance, activity and maintenance over time) would reinforce confidence in the use of experimental transporter/barrier systems as well as in established cell-based toxicological assays currently used for CRA

Construction of cryptogein mutants, a proteinaceous elicitor from Phytophthora, with altered abilities to induce a defense reaction in tobacco cells

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Environmental and health risk assessments of additives polyethylene plastics

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