Ontogeny of Human Liver Aldehyde Oxidase: Developmental Changes and Implications for Drug Metabolism.

Document Type

Article

Publication Date

6-3-2024

Identifier

DOI: 10.1021/acs.molpharmaceut.3c01147

Abstract

Despite the increasing importance of aldehyde oxidase (AO) in the drug metabolism of clinical candidates, ontogeny data for AO are limited. The objective of our study was to characterize the age-dependent AO content and activity in the human liver cytosolic fraction (HLC) and human hepatocytes (HH). HLC (n = 121 donors) and HH (n = 50 donors) were analyzed for (1) AO protein content by quantitative proteomics and (2) enzyme activity using carbazeran as a probe substrate. AO activity showed high technical variability and poor correlation with the content in HLC samples, whereas hepatocyte samples showed a strong correlation between the content and activity. Similarly, AO content and activity showed no significant age-dependent differences in HLC samples, whereas the average AO content and activity in hepatocytes increased significantly (∼20-40-fold) from the neonatal levels (0-28 days). Based on the hepatocyte data, the age at which 50% of the adult AO content is reached (age50) was 3.15 years (0.32-13.97 years, 95% CI). Metabolite profiling of carbazeran revealed age-dependent metabolic switching and the role of non-AO mechanisms (glucuronidation and desmethylation) in carbazeran elimination. The content-activity correlation in hepatocytes improved significantly (R2 = 0.95; p < 0.0001) in samples showing

Journal Title

Molecular pharmaceutics

Volume

21

Issue

6

First Page

2740

Last Page

2750

MeSH Keywords

Humans; Aldehyde Oxidase; Hepatocytes; Liver; Child; Infant; Adult; Child, Preschool; Adolescent; Infant, Newborn; Male; Young Adult; Female; Middle Aged; Cytosol; Proteomics

Keywords

aldehyde oxidase; drug metabolism; ontogeny; quantitative proteomics

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