Expression profile of cytochrome P450s and effects of polycyclic aromatic hydrocarbons and antiepileptic drugs on CYP1 expression in MOG-G-CCM cells

Life Sci. 2020 Oct 1:258:118140. doi: 10.1016/j.lfs.2020.118140. Epub 2020 Jul 27.

Abstract

Aims: This study was performed to investigate the expression profile of cytochrome P450 (CYP) isoforms and effects of polycyclic aromatic hydrocarbons (PAHs) and antiepileptic drugs on CYP1 expression in human astrocytoma MOG-G-CCM cells.

Main methods: CYP1A1 and CYP1B1 expression were determined by quantitative real-time polymerase chain reaction, Western blotting, and immunocytochemistry.

Key findings: MOG-G-CCM cells expressed various CYP isoforms. Among the CYP isoforms analyzed, CYP1B1 showed the highest expression level, followed by CYP1A1. Furthermore, CYP1B1 was localized in both the endoplasmic reticulum and mitochondria. 3-Methylcholanthrene (3-MC), benz[a]anthracene (B[a]A), benzo[a]pyrene (B[a]P), and valproic acid (VPA) increased the expression of CYP1B1 and CYP1A1. The potent aryl hydrocarbon receptor antagonist GNF351 significantly suppressed the 3-MC- and VPA-mediated upregulation of CYP1B1 and CYP1A1. In addition, VPA potentiated the induction of CYP1B1 and CYP1A1 by 3-MC, B[a]A, and B[a]P, although the augmentation of CYP1A1 was more remarkable than that of CYP1B1. In contrast, other antiepileptic drugs (carbamazepine, lamotrigine, levetiracetam, phenytoin) did not affect the 3-MC-mediated upregulation of CYP1B1 and CYP1A1. VPA is known to act as a histone deacetylase (HDAC) inhibitor. Therefore, the effects of trichostatin A, a representative HDAC inhibitor, on CYP1 induction by 3-MC were examined. Trichostatin A enhanced the 3-MC-mediated upregulation of CYP1A1 but not CYP1B1.

Significance: These results partially indicated that VPA may augment the PAH-mediated induction of CYP1B1 and CYP1A1 through the activation of transcription by HDAC inhibition.

Keywords: Antiepileptic drugs; Aryl hydrocarbon receptor; Astrocytes; CYP1A1; CYP1B1; Histone deacetylase inhibition; Induction; Polycyclic aromatic hydrocarbons.

MeSH terms

  • Anticonvulsants / pharmacology*
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Cell Line, Tumor
  • Cytochrome P-450 CYP1A1 / genetics*
  • Cytochrome P-450 CYP1B1 / genetics*
  • Humans
  • Polycyclic Aromatic Hydrocarbons / pharmacology*
  • Transcriptome / drug effects
  • Up-Regulation / drug effects*
  • Valproic Acid / pharmacology*

Substances

  • Anticonvulsants
  • Polycyclic Aromatic Hydrocarbons
  • Valproic Acid
  • CYP1A1 protein, human
  • CYP1B1 protein, human
  • Cytochrome P-450 CYP1A1
  • Cytochrome P-450 CYP1B1