Oxidative stress-responsive transcription factor NRF2 is not indispensable for the human hepatic Flavin-containing monooxygenase-3 (FMO3) gene expression in HepG2 cells

Abstract

The flavin-containing monooxygenases (FMOs) are important for the oxidation of a variety of endogenous compounds and xenobiotics. The hepatic expression of FMO3 is highly variable and until recently, it was thought to be uninducible. In this study, human FMO3 gene regulation by the oxidative stress transcription factor, nuclear factor (erythroid-derived 2)-like 2 (NRF2) was examined. Constitutive FMO3 gene expression is repressed in HepG2 cells, thus this cell can be a good model for FMO3 gene regulation studies. Over-expression of NRF2 in HepG2 cells increased NRF2 target gene expression, heme oxygenase-1 (HMOX1) and NAD(P)H:quinone oxidoreductase-1 (NQO1), but did not alter FMO3 gene expression. Co-transfection studies with NRF2 or its cytosolic regulatory protein, Kelch-like ECH-associated protein 1 (KEAP1), expression vectors, along with FMO3 promoter luciferase reporter constructs of various lengths (5Kb or 6Kb), did not change FMO3 reporter gene activity significantly. Furthermore, treatment with tert-butyl hydroperoxide (tBHP) and tert-butyl hydroquinone (tBHQ) did not alter FMO3 reporter construct activity. In summary, in vitro results suggest that the transcriptional regulation of FMO3 might not involve the NRF2-KEAP1 regulatory pathway.

From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective

“…We have shown that induction of Mrp4 during APAP hepatotoxicity is dependent on Nrf2 29 . On the contrary, the induction of FMO3 is not regulated by Nrf2 30 . Furthermore, deletion of Nrf2 alone does not abolish APAP autoprotection, since Nrf2-null mice develop tolerance to APAP hepatotoxicity similar to wild-type mice ( 14 and unpublished data from our laboratory).…”

Identification of a novel oxidative stress-related prognostic model in lung adenocarcinoma

“…Moreover, the CYP2D6 genotypes can predict Tamoxifen discontinuation and prognosis in patients with breast cancer (He et al, 2020). FM O 3 is an important oxidative drug metabolizing enzyme, which is Closely related to oxidative stress-responsive transcription factor NRF2 (Klick and Hines, 2007;Rudraiah et al, 2016). Meanwhile, FM O 3 has been reported to be investigated as a prognostic marker in hepatocellular carcinoma (Zhu et al, 2021).…”