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Omeprazole transactivates human CYP1A1 and CYP1A2 expression through the common regulatory region containing multiple

Kouichi Yoshinari1, Rika Ueda, Kazutomi Kusano

  • 1Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan.

Biochemical Pharmacology
|May 27, 2008
PubMed

Insights

Omeprazole induces CYP1A1 and CYP1A2 via a shared regulatory region, but its mechanism differs from typical aryl hydrocarbon receptor (AHR) ligands like BNF and 3MC. This study identifies the specific DNA region responsible for this induction.

Area of Science:

  • Pharmacology and Toxicology
  • Molecular Biology
  • Drug Metabolism

Background:

  • Omeprazole induces human CYP1A1 and CYP1A2, enzymes involved in drug metabolism.
  • Aryl hydrocarbon receptor (AHR) mediates this induction, but the precise mechanism is unclear as omeprazole does not directly bind AHR like typical ligands (e.g., 3-methylcholanthrene [3MC], beta-naphthoflavone [BNF]).
  • Human CYP1A1 and CYP1A2 genes share a common 5'-flanking regulatory region.

Purpose of the Study:

  • To identify the specific DNA region responsible for omeprazole-induced CYP1A1 and CYP1A2 expression.
  • To elucidate the molecular mechanism of omeprazole's induction of these enzymes.
  • To compare the induction profiles of omeprazole with known AHR ligands.

Main Methods:

  • Transient transfection assays using single and dual reporter gene constructs containing the shared 5'-flanking region of human CYP1A1 and CYP1A2.
  • Reporter assays with deletion constructs to map the omeprazole-responsive regulatory region.
  • Simultaneous measurement of CYP1A1 and CYP1A2 transcriptional activities.

Main Results:

  • Omeprazole-induced expression of both CYP1A1 and CYP1A2 is mediated by a common regulatory region (-464 to -1829 of human CYP1A1), identical to the BNF/3MC-responsive region.
  • Omeprazole induced CYP1A1 and CYP1A2 to similar extents, whereas BNF and 3MC preferentially induced CYP1A1.
  • Primaquine acted as an omeprazole-like inducer, while lansoprazole and albendazole showed BNF/3MC-like preferences.

Conclusions:

  • Omeprazole, BNF, and 3MC activate human CYP1A1 and CYP1A2 expression through the same regulatory region.
  • Omeprazole's induction mechanism may involve different cellular signaling pathways compared to BNF and 3MC.
  • The study provides insights into the differential regulation of CYP1A1 and CYP1A2 by various compounds.

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