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Published on: January 27, 2023
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Hepatic Cytochrome P450 Activity, Abundance, and Expression Throughout Human Development
Natalie C Sadler1, Premchendar Nandhikonda1, Bobbie-Jo Webb-Robertson1
1Biological Sciences Division (N.C.S., P.N., C.A., L.N.A., J.N.S., R.A.C., A.T.W.) and Computational and Statistical Analytics Division (B.J.W.R.), Pacific Northwest National Laboratory, Richland, Washington.
Summary
This study reveals how cytochrome P450 (CYP) enzyme activity changes during human development. Understanding CYP ontogeny is key for predicting drug and environmental chemical effects.
Area of Science:
- Biochemistry
- Pharmacology
- Developmental Biology
Background:
- Cytochrome P450 (CYP) enzymes are crucial for metabolizing compounds.
- CYP expression and activity vary significantly during human development.
- Limited understanding of CYP ontogeny hinders prediction of exposure effects.
Purpose of the Study:
- To comprehensively characterize the ontogeny of CYP enzymes.
- To investigate CYP transcript expression, protein abundance, and functional activity across human development.
- To establish a functional profile of CYP ontogeny.
Main Methods:
- Multi-omic characterization of CYP enzymes.
- Use of modified mechanism-based inhibitors as chemical probes.
- High-resolution liquid chromatography-mass spectrometry (LC-MS) for quantifying probe-labeled CYPs.
- Measurement of total protein abundance and CYP rRNA.
Main Results:
- Detailed functional profiling of CYP ontogeny from early gestation to adulthood.
- Demonstrated life-stage-dependent variability in CYP expression, abundance, and activity.
- Identified frequent discordant relationships between CYP expression and activity.
Conclusions:
- Expanded knowledge of CYP ontogeny, especially individual enzyme activity.
- Results aid in predicting therapeutic dosing and avoiding adverse reactions to drugs and xenobiotics during maturation.
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