title: Aldehyde oxidase activity in fresh human skin.
abstract: 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 (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 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.
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Nenad
authors.initials: N
authors.lastname: Manevski
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Kamal Kumar
authors.initials: KK
authors.lastname: Balavenkatraman
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Bertschi
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Piet
authors.initials: P
authors.lastname: Swart
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Markus
authors.initials: M
authors.lastname: Walles
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Gian
authors.initials: G
authors.lastname: Camenisch
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Hilmar
authors.initials: H
authors.lastname: Schiller
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Olivier
authors.initials: O
authors.lastname: Kretz
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Barbara
authors.initials: B
authors.lastname: Ling
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Reto
authors.initials: R
authors.lastname: Wettstein
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Schaefer
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Francois
authors.initials: F
authors.lastname: Pognan
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.).
authors.forename: Armin
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Drug Metabolism and Pharmacokinetics (N.M., P.S., M.W., G.C., H.S., O.K., K.L.) and Pre-clinical Safety (K.K.B., B.B., F.P., A.W.), Novartis Institutes for BioMedical Research, Novartis Pharma, Basel, Switzerland; and Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, University Hospital Basel, Basel, Switzerland (B.L., R.W., D.J.S.) Karine.Litherland@novartis.com.
authors.forename: Karine
authors.initials: K
authors.lastname: Litherland
mesh_terms: D000328:Adult; D000368:Aged; D042931:Aldehyde Oxidase / Q000378:metabolism*; D002219:Carbamates / Q000378:metabolism; D005260:Female; D006146:Guanidines / Q000378:metabolism; D006801:Humans; D006830:Hydralazine / Q000378:metabolism; D006900:Hydroxylation / Q000502:physiology; D007700:Kinetics; D008297:Male; D050217:Metabolic Detoxication, Phase II / Q000502:physiology; D008875:Middle Aged; D011720:Pyrazoles / Q000378:metabolism; D012867:Skin / Q000201:enzymology* / Q000378:metabolism*; D014052:Toluidines / Q000378:metabolism
chemical_list: D002219:Carbamates; D006146:Guanidines; D011720:Pyrazoles; D014052:Toluidines; C031720:carbazeran; D006830:Hydralazine; C424422:zoniporide; D042931:Aldehyde Oxidase; C029370:4-toluidine