Aldehyde oxidase activity in fresh human skin

Area of Science:

• Pharmacology
• Drug Metabolism
• Biochemistry

Background:

• Human aldehyde oxidase (AO) is crucial for metabolizing many drugs containing azaheterocycles.
• High AO activity contributes to drug clearance, but its role outside the liver (extrahepatic) is poorly understood.
• Existing in vitro-in vivo correlations for AO drug metabolism are often unreliable.

Purpose of the Study:

• To investigate the enzymatic activity of aldehyde oxidase (AO) in fresh human skin.
• To determine the significance of AO in cutaneous drug metabolism and xenobiotic exposure.
• To assess the kinetic properties and interindividual variability of AO in skin.

Main Methods:

• Human skin explants from 13 donors were used to assay AO activity.
• Specific AO substrates, carbazeran and zoniporide, were incubated with skin samples.
• Metabolite formation was quantified, and enzyme kinetics were analyzed, including inhibition studies with hydralazine.

Main Results:

• Human skin explants from all donors demonstrated metabolism of carbazeran and zoniporide.
• Significant hydroxylation rates were observed, with interindividual variability ranging from 3- to 6-fold.
• AO activity in skin was comparable to tested Phase II metabolic reactions, indicating a substantial role in cutaneous drug metabolism.

Conclusions:

• This study provides the first evidence of functional aldehyde oxidase (AO) enzymatic activity in human skin.
• Cutaneous AO plays a significant role in the metabolism of drugs and xenobiotics, impacting their efficacy and safety.
• Understanding extrahepatic AO activity in skin is critical for improving drug development and predicting in vivo outcomes.