Manevski, Nenad, Balavenkatraman, Kamal Kumar, Bertschi, Barbara, Swart, Pieter Jacob, Walles, Markus, Camenisch, Gian P., Schiller, Hilmar, Kretz, Olivier, Ling, Barbara, Wettstein, Reto, Schaefer, Dirk J., Pognan, Francois, Wolf, Armin and Litherland, Karine (2015) Aldehyde oxidase activity in human skin explants. Drug Metabolism and Disposition.

Abstract

Human aldehyde oxidase (AO) is a molybdo-flavoenzyme that commonly oxidizes azaheterocycles in therapeutic drugs. Although high metabolic clearance by AO resulted in drug failures, existing in vitro–in vivo correlations are often poor and extrahepatic role of AO is practically unknown. This study investigated enzymatic activity of AO in 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% of substrate turnover after 24 h of incubation with 10 μM of substrate, respectively. Hydroxylation activities for the two substrates were significantly correlated (r2 = 0.769), with interindividual variability ranging from 3 (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 of the inhibitor. Reaction rates were linear up to 4 h 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.

Item Type:	Article
Keywords:	Aldehyde oxidase; Phase I drug metabolism; human skin; skin explants; biotransformation; zoniporide; carbazeran; hydralazine
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/22896