Characterization of ABC transporters in  human skin

Osman‐Ponchet, Hanan; Boulai, Anaïs; Kouidhi, Magali; Sevin, Karine; Alriquet, Marion; Gaborit, Alexandre; Bertino, Béatrice; Comby, Pierre; Ruty, Bernard

doi:10.1515/dmdi-2013-0042

Cited by 35 publications

(39 citation statements)

References 33 publications

(47 reference statements)

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“…4), not the skin explants, suggested that phase II metabolites are actively excreted from the skin, diminishing the product inhibition within the cells. This hypothesis is supported by a recent finding that human skin expresses a number of ATP-binding cassette efflux transporters, particularly multidrug resistance-associated protein 1 (MRP1/ABCC1) (Osman-Ponchet et al, 2014).…”

Section: Discussionmentioning

confidence: 81%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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Although skin is the largest organ of the human body, cutaneous drug metabolism is often overlooked, and existing experimental models are insufficiently validated. This proof-of-concept study investigated phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model containing all skin cell types. Results show that skin explants have significant capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Novel skin metabolites were identified, including acyl glucuronides of indomethacin and diclofenac, glucuronides of 17b-estradiol, N-acetylprocainamide, and methoxy derivatives of 4-nitrocatechol and 2,3-dihydroxynaphthalene. Measured activities for 10 mM substrate incubations spanned a 1000-fold: from the highest 4.758 pmol·mg skin ·h -1 for 17b-estradiol 17-glucuronidation. Interindividual variability was 1.4-to 13.0-fold, the highest being 4-methylumbelliferone and diclofenac glucuronidation. Reaction rates were generally linear up to 4 hours, although 24-hour incubations enabled detection of metabolites in trace amounts. All reactions were unaffected by the inclusion of cosubstrates, and freezing of the fresh skin led to loss of glucuronidation activity. The predicted whole-skin intrinsic metabolic clearances were significantly lower compared with corresponding whole-liver intrinsic clearances, suggesting a relatively limited contribution of the skin to the body's total systemic phase II enzymemediated metabolic clearance. Nevertheless, the fresh full-thickness skin explants represent a suitable model to study cutaneous phase II metabolism not only in drug elimination but also in toxicity, as formation of acyl glucuronides and sulfate conjugates could play a role in skin adverse reactions.

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Section: Discussionmentioning

confidence: 81%

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

et al. 2014

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“…The extensive expression of MATE1 transporter in human skin and the down-regulation by solar simulator exposure suggest that this transporter might serve as a biomarker for skin cancers, particularly those induced by solar exposure. Furthermore, the expression of MATE1 transporter in human skin may play an important role in chemosensitivity of cutaneous cancer cells and thus may be the basis for the discovery of novel agents for the treatment of skin cancers [28].…”

Section: Discussionmentioning

confidence: 99%

“…Recently the expression pattern of human ATP-binding cassette transporters was reported in human skin [16]. In addition the characterization of ABC transporters in human skin was reported recently by our group [17].…”

Section: Introductionmentioning

confidence: 90%

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Characterization of SLC transporters in human skin

Alriquet¹,

Sevin²,

Gaborit³

et al. 2015

ADMET DMPK

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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)

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“…Interestingly, the predominant extracellular localization of metabolites after 24 hours indicated that 4-hydroxycarbazeran and 2-oxo-zoniporide are excreted from the skin cells, either by passive diffusion or active transport. Osman-Ponchet et al (2014) recently reported expression and activity of a number of efflux transporters in the human skin, most notably multidrug resistance-associated protein 1.…”

Section: Discussionmentioning

confidence: 99%

Aldehyde Oxidase Activity in Fresh Human Skin

et al. 2014

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Human aldehyde oxidase (AO) is a molybdoflavoenzyme that commonly oxidizes azaheterocycles in therapeutic drugs. Although high metabolic clearance by AO resulted in several drug failures, existing in vitro-in vivo correlations are often poor and the extrahepatic role of AO practically unknown. This study investigated enzymatic activity of AO in fresh human skin, the largest organ of the body, frequently exposed to therapeutic drugs and xenobiotics. Fresh, full-thickness human skin was obtained from 13 individual donors and assayed with two specific AO substrates: carbazeran and zoniporide. Human skin explants from all donors metabolized carbazeran to 4-hydroxycarbazeran and zoniporide to 2-oxo-zoniporide. Average rates of carbazeran and zoniporide hydroxylations were 1.301 and 0.164 pmol×mg skin, resulting in 13 and 2% substrate turnover, respectively, after 24 hours of incubation with 10 mM substrate. Hydroxylation activities for the two substrates were significantly correlated (r 2 = 0.769), with interindividual variability ranging from 3-fold (zoniporide) to 6-fold (carbazeran). Inclusion of hydralazine, an irreversible inhibitor of AO, resulted in concentration-dependent decrease of hydroxylation activities, exceeding 90% inhibition of carbazeran 4-hydroxylation at 100 mM inhibitor. Reaction rates were linear up to 4 hours and well described by MichaelisMenten enzyme kinetics. Comparison of carbazeran and zoniporide hydroxylation with rates of triclosan glucuronidation and sulfation and p-toluidine N-acetylation showed that cutaneous AO activity is comparable to tested phase II metabolic reactions, indicating a significant role of AO in cutaneous drug metabolism. To our best knowledge, this is the first report of AO enzymatic activity in human skin.

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Characterization of ABC transporters in human skin

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

Cited by 35 publications

References 33 publications

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Phase II Metabolism in Human Skin: Skin Explants Show Full Coverage for Glucuronidation, Sulfation,N-Acetylation, Catechol Methylation, and Glutathione Conjugation

Characterization of SLC transporters in human skin

Aldehyde Oxidase Activity in Fresh Human Skin

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