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5-ALA treatment increases intracellular heme levels and enhances CYP3A4 activity in genome-edited Caco-2 cells

Watanabe, Keita ; Negoro, Ryosuke ; Fujita, Takuya

Biochemical and biophysical research communications, 2023-07, Vol.664, p.94-99 [Periódico revisado por pares]

United States: Elsevier Inc

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  • Título:
    5-ALA treatment increases intracellular heme levels and enhances CYP3A4 activity in genome-edited Caco-2 cells
  • Autor: Watanabe, Keita ; Negoro, Ryosuke ; Fujita, Takuya
  • Assuntos: 5-ALA ; Aminolevulinic Acid - pharmacology ; Caco-2 Cells ; Caco-2 cell ; CYP3A4 ; Cytochrome P-450 CYP3A - genetics ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P-450 Enzyme System - metabolism ; Drug-metabolizing enzyme ; Heme ; Humans
  • É parte de: Biochemical and biophysical research communications, 2023-07, Vol.664, p.94-99
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: In nonclinical studies, models that can predict the metabolism of drug candidates by cytochrome P450 (CYP), including Cytochrome P450 family 3 subfamily A member 4 (CYP3A4) are helpful. CYP3A4-overexpressing human cells have been used universally to evaluate whether CYP3A4 metabolizes drug-candidate compounds. However, CYP3A4-overexpressing human cell lines are problematic because their activity levels are lower than that of in vivo human CYP3A4. Heme plays a paramount role in CYP activity. The rate-limiting step in heme biosynthesis is the generation of 5-aminolevulinic acid (5-ALA). In this study, we examined whether treatment with 5-ALA to CYP3A4-POR-UGT1A1-CES2 knockin and CES1 knockout (genome-edited) Caco-2 cells enhances CYP3A4 activity. A 7-day 5-ALA treatment increased intracellular heme levels in genome-edited Caco-2 cells without cytotoxicity. Moreover, consistent with the increase in intracellular heme content, 5-ALA treatment increased CYP3A4 activity in genome-edited Caco-2 cells. The results of this research are expected to be applied to pharmacokinetic studies using CYP-overexpressing human cells containing CYP3A4. •5-ALA treatment increased intracellular heme levels in genome-edited Caco-2 cells.•Long-term 5-ALA treatment in genome-edited Caco-2 cells resulted in toxicity.•5-ALA treatment increased CYP3A4 activity in genome-edited Caco-2 cells.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
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