Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development

Abstract

Cytochrome P450s are oxidative metabolic enzymes that play critical roles in the biotransformation of endogenous compounds and xenobiotics. The expression and activity of P450 enzymes varies considerably throughout human development; the deficit in our understanding of these dynamics limits our ability to predict environmental and pharmaceutical exposure effects. In an effort to develop a more comprehensive understanding of the ontogeny of P450 enzymes, we employed a multi-omic characterization of P450 transcript expression, protein abundance, and functional activity. Modified mechanism-based inhibitors of P450s were used as chemical probes for isolating active P450 proteoforms in human hepatic microsomes with developmental stages ranging from early gestation to late adult. High-resolution liquid chromatography-mass spectrometry was used to identify and quantify probe-labeled P450s, allowing for a functional profile of P450 ontogeny. Total protein abundance profiles and P450 rRNA was also measured, and our results reveal life-stage-dependent variability in P450 expression, abundance, and activity throughout human development and frequent discordant relationships between expression and activity. We have significantly expanded the knowledge of P450 ontogeny, particularly at the level of individual P450 activity. We anticipate that these results will be useful for enabling predictive therapeutic dosing, and for avoiding potentially adverse and harmful reactions during maturation from both therapeutic drugs and environmental xenobiotics.

Pharmacogenomic findings from clinical whole exome sequencing of diagnostic odyssey patients

“…The transition of the CYP2C expression to adult levels throughout childhood is poorly understood (Treluyer et al 2000;Hines and McCarver 2002). This is further complicated by recent studies showing that CYP protein expression and enzyme activity can be discordant (Sadler et al 2016). While we understand that these differences by age and stage of development exist, contributing to therapeutic variability, our ability to predict the appropriate dosing requirements by these developmental differences is understudied and limited (Hines and McCarver 2002).…”

A Comprehensive Overview of the Clinical Pharmacokinetics of Clobazam

“…In order to predict CLB dosing for younger pediatric patients whose ability to metabolize CLB and other drugs differs from that of adults, a third PopPK analysis was developed that incorporated weight and ontogeny . Data from 4 studies, including a bioequivalence study in healthy subjects, a phase 3 efficacy trial in patients with LGS, an observational study in patients with LGS, and a simulated study, were pooled for this analysis.…”

The effects of maternal antidepressant use on offspring behaviour and brain development: Implications for risk of neurodevelopmental disorders

“…Studies examining SSRI concentrations in foetal cord blood from treated mothers have reported concentrations of at least 50% compared to maternal levels (for review see Ewing et al, 2015). Additionally, two enzymes responsible for the metabolism of SSRIs in humans, cytochrome P450 2C and 2D6 (CYP2C and CYP2D6), are low or undetectable in the foetal liver but increase progressively during early life (Hines and McCarver, 2002;Sadler et al, 2016). Therefore, the foetus and neonate may be particularly sensitive to maternal SSRI exposure due to an inability to eliminate drugs through metabolism by the liver (Hiemke and Härtter, 2000;Kim et al, 2006).…”