Manevski, Nenad, Swart, Pieter Jacob, Balavenkatraman, Kamal Kumar, Bertschi, Barbara, Camenisch, Gian P., Kretz, Olivier, Schiller, Hilmar, Walles, Markus, Barbara , Ling, Reto , Wettstein, Dirk J, Schaefer, Peter, Itin, Chess, Joanna, Pognan, Francois, Wolf, Armin and Litherland, Karine (2014) Phase II Metabolism in Human skin: Skin Explants Show Activities of Glucuronidation, Sulfation, N-Acetylation, Catechol Methylation, and Glutathione Conjugation. Biochemical Pharmacology.

Abstract

Although skin is the largest organ of the human body, drug metabolism in skin tissue is often overlooked and existing experimental models tend to lack sufficient validation. To address these challenges, we studied phase II biotransformation of 11 test substrates in fresh full-thickness human skin explants, a model that contains all skin cell types. Results show that human skin has substantial capacity for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Novel skin metabolites were identified and quantified, including acyl glucuronides of indomethacin and diclofenac, glucuronides of 17β estradiol, and methoxy derivatives of 4-nitrocatechol and 2,3-dihydroxynaphthalene. Measured activities for 10 μM substrate incubations spanned almost a 1000-fold: from the highest 4.758 pmol•mg skin–1•h–1 for p toluidine N-acetylation to the lowest 0.006 pmol•mg skin–1•h–1 for 17β estradiol 17 glucuronidation. Interindividual variability was 1.4 to 13.0-fold, depending on the test substrate, being the highest for 4-methylumbelliferone and diclofenac glucuronidation. Reaction rates were generally linear up to 4 h, although 24 h incubations enabled detection of metabolites in trace amounts. Phase II reactions were unaffected by the inclusion of cosubstrates, but glucuronidation activity was absent following skin freezing. Activities were higher for lower molecular weight substrates with solvent-accessible surface area below 300 Å2 and polar surface area below 50 Å2. Taken together, the fresh full-thickness skin explants represent an appropriate model to study cutaneous phase II metabolism. Although phase II biotransformation mainly results in drug elimination and detoxification, formation of acyl glucuronides and sulfate conjugates could also play a potential role in skin toxicity processes.

Item Type:	Article
Keywords:	Human skin, skin explants, phase II metabolism, detoxification, extrahepatic metabolism, drug conjugation
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22442