TY - JOUR T1 - Aldehyde Oxidase Activity in Fresh Human Skin JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 2049 LP - 2057 DO - 10.1124/dmd.114.060368 VL - 42 IS - 12 AU - Nenad Manevski AU - Kamal Kumar Balavenkatraman AU - Barbara Bertschi AU - Piet Swart AU - Markus Walles AU - Gian Camenisch AU - Hilmar Schiller AU - Olivier Kretz AU - Barbara Ling AU - Reto Wettstein AU - Dirk J. Schaefer AU - Francois Pognan AU - Armin Wolf AU - Karine Litherland Y1 - 2014/12/01 UR - http://dmd.aspetjournals.org/content/42/12/2049.abstract N2 - 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–1⋅h–1, resulting in 13 and 2% substrate turnover, respectively, after 24 hours of incubation with 10 μM substrate. Hydroxylation activities for the two substrates were significantly correlated (r2 = 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 μM inhibitor. Reaction rates were linear up to 4 hours and well described by Michaelis-Menten 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. ER -