Screening towards a CYP3A7-specific marker reaction against CYP3A4 and CYP3A5

Authors

• EC Padilha
• P Shah
• X Xu

Abstract

CYP3A4 is the primary CYP450 enzyme for xenobiotic metabolism, but CYP3A7 is predominant in human embryonic, fetal, and newborn liver and remains underexplored. Currently, to evaluate CYP3A7 activity substrates like testosterone and dehydroepiandrosterone sulfate (DHEAS) are used, however, they are also metabolized by CYP3A4, making it difficult to find a selective marker for CYP3A7, similar to the challenge with CYP3A4 and CYP3A5 due to substrate overlap. Therefore, identifying a specific marker substrate for CYP3A7 is crucial.
We screened around 3300 compounds, including FDA-approved drugs and drug-like molecules, using CYP3A4 and CYP3A7 supersomes. We identified 64 compounds with a half-life (t1/2) less than 30 minutes for CYP3A7 and more than 30 minutes for CYP3A4. Further, we tested these compounds against CYP3A4, CYP3A5, and CYP3A7 supersomes and identified 8 compounds with minimal depletion in CYP3A4 and CYP3A5 but significant depletion in CYP3A7. Metabolite identification (MetID) studies revealed that NCGC00179658 produced a unique metabolite with CYP3A7, indicating its potential as a marker substrate.
However, when NCGC00179658 was incubated with human liver microsomes, including those from 8 infant donors under 1 year old with presumably elevated CYP3A7 activity, the unique CYP3A7 metabolite was not generated in measurable amounts. This study details our efforts to find a CYP3A7 marker substrate and its application in liver microsomal incubations, along with MetID data for the 8 compounds with shorter t1/2 in 3A7 compared to 3A4 in supersome incubations.

Scientific Focus Area: Molecular Pharmacology

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