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Article

Calcitriol Induces Paraoxonase 1 Expression in HepG2 Cells: Possible Involvement of VDR-Dependent and Alternative Pathways

by
Fidel Navarro-García
1,
Aurora E. Rojas-García
2,
Gabriela Ávila-Villarreal
3,4,
Sergio Hidalgo-Figueroa
5,
Briscia S. Barrón-Vivanco
2,
Cyndia A. González-Arias
2,
Yael Y. Bernal-Hernández
2,
José F. Herrera-Moreno
2,6,
Guillermo Elizondo
7,
José L. Medina-Franco
8 and
Irma M. Medina-Díaz
2,*
1
Posgrado en Ciencias Biológico Agropecuarias, Universidad Autónoma de Nayarit, Km. 9 Carretera Tepic-Compostela, Xalisco 63780, Nayarit, Mexico
2
Laboratorio de Contaminación y Toxicología Ambiental, Secretaría de Investigación y Posgrado, Universidad Autónoma de Nayarit, Tepic 63000, Nayarit, Mexico
3
Unidad Académica de Ciencias Químico Biológicas y Farmacéuticas, Universidad Autónoma de Nayarit, Tepic 63000, Nayarit, Mexico
4
Centro Nayarita de Innovación y Transferencia de Tecnología “Unidad especializada en I+D+i en Calidad de Alimentos y Productos Naturales”, Universidad Autónoma de Nayarit, Tepic 63000, Nayarit, Mexico
5
CONACYT-División de Biología Molecular, Instituto Potosino de Investigación Científica y Tecnológica A.C., San Luis Potosí 78000, San Luis Potosí, Mexico
6
Secretaría de Ciencia, Humanidades, Tecnología e Innovación (SECIHTI), Padrón de Investigadoras e Investigadores por México, Mexico City 03940, Mexico
7
Departamento de Biología Celular, CINVESTAV-IPN, Mexico City 07360, Mexico
8
Grupo de Investigación DIFACQUIM, Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(16), 7948; https://doi.org/10.3390/ijms26167948
Submission received: 17 July 2025 / Revised: 5 August 2025 / Accepted: 15 August 2025 / Published: 18 August 2025
(This article belongs to the Special Issue Molecular Insights into Toxicity: Identifying Biomarkers and Molecular Pathways Involved in Toxicological Responses)
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Abstract

Paraoxonase 1 (PON1) is an antioxidant enzyme that plays physio-pathological roles. Prior in silico analysis revealed the presence of response elements of the nuclear receptor superfamily in the PON1 promoter, comparable to glucocorticoid receptors (GR), the vitamin D receptor (VDR), and the pregnenolone X receptor (PXR). The aim of this study was to evaluate the effects of 1α,25-dihydroxyvitamin D3, a ligand specific to VDR, on the expression and activity of PON1 in hepatocarcinoma cells (HepG2 cells). PON1 activities (arylesterase/AREase and lactonase/LACase) were determined by spectrophotometry. Quantitative real-time PCR was used to evaluate the effect of VDR and PXR on the mRNA levels of PON1 and CYP3A4 genes. Molecular models and dynamics simulations were built using specialized software. Treatments with 1α,25-dyhydroxyvitamin D3 (calcitriol), its active hormonal form, resulted in an induction of PON1 mRNA and AREase activity compared to control cultures. These results suggest that calcitriol plays a role in the regulation of PON1 transcription and provide evidence that this hormone increases PON1 levels in HepG2 cells. In addition, the molecular modeling suggests that calcitriol enhances PON1 activity and this increase could be caused by direct interaction on the PON1 protein. This study shows the effects of calcitriol on PON1 expression, proposing a new molecular mechanism for the transcriptional regulation of PON1 through a process linked to VDR activation and direct interaction of calcitriol on the PON1 protein.
Keywords: paraoxonase 1; calcitriol; gene expression; enzymatic activity; vitamin D receptor; pregnenolone X receptor paraoxonase 1; calcitriol; gene expression; enzymatic activity; vitamin D receptor; pregnenolone X receptor

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MDPI and ACS Style

Navarro-García, F.; Rojas-García, A.E.; Ávila-Villarreal, G.; Hidalgo-Figueroa, S.; Barrón-Vivanco, B.S.; González-Arias, C.A.; Bernal-Hernández, Y.Y.; Herrera-Moreno, J.F.; Elizondo, G.; Medina-Franco, J.L.; et al. Calcitriol Induces Paraoxonase 1 Expression in HepG2 Cells: Possible Involvement of VDR-Dependent and Alternative Pathways. Int. J. Mol. Sci. 2025, 26, 7948. https://doi.org/10.3390/ijms26167948

AMA Style

Navarro-García F, Rojas-García AE, Ávila-Villarreal G, Hidalgo-Figueroa S, Barrón-Vivanco BS, González-Arias CA, Bernal-Hernández YY, Herrera-Moreno JF, Elizondo G, Medina-Franco JL, et al. Calcitriol Induces Paraoxonase 1 Expression in HepG2 Cells: Possible Involvement of VDR-Dependent and Alternative Pathways. International Journal of Molecular Sciences. 2025; 26(16):7948. https://doi.org/10.3390/ijms26167948

Chicago/Turabian Style

Navarro-García, Fidel, Aurora E. Rojas-García, Gabriela Ávila-Villarreal, Sergio Hidalgo-Figueroa, Briscia S. Barrón-Vivanco, Cyndia A. González-Arias, Yael Y. Bernal-Hernández, José F. Herrera-Moreno, Guillermo Elizondo, José L. Medina-Franco, and et al. 2025. "Calcitriol Induces Paraoxonase 1 Expression in HepG2 Cells: Possible Involvement of VDR-Dependent and Alternative Pathways" International Journal of Molecular Sciences 26, no. 16: 7948. https://doi.org/10.3390/ijms26167948

APA Style

Navarro-García, F., Rojas-García, A. E., Ávila-Villarreal, G., Hidalgo-Figueroa, S., Barrón-Vivanco, B. S., González-Arias, C. A., Bernal-Hernández, Y. Y., Herrera-Moreno, J. F., Elizondo, G., Medina-Franco, J. L., & Medina-Díaz, I. M. (2025). Calcitriol Induces Paraoxonase 1 Expression in HepG2 Cells: Possible Involvement of VDR-Dependent and Alternative Pathways. International Journal of Molecular Sciences, 26(16), 7948. https://doi.org/10.3390/ijms26167948

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