Immunization and Drug Metabolizing Enzymes: Focus on Hepatic Cytochrome P450 3A

ABSTRACT

Objective

Infectious disease emergencies like the 2013–2016 Ebola epidemic and the 2009 influenza and current SARS-CoV-2 pandemics illustrate that vaccines are now given to diverse populations with preexisting pathologies requiring pharmacological management. Many natural biomolecules (steroid hormones, fatty acids, vitamins) and ~60% of prescribed medications are processed by hepatic cytochrome P450 (CYP) 3A4. The objective of this work was to determine the impact of infection and vaccines on drug metabolism.

Methods

The impact of an adenovirus-based vaccine expressing Ebola glycoprotein (AdEBO) and H1N1 and H3N2 influenza viruses on hepatic CYP 3A4 and associated nuclear receptors was evaluated in human hepatocytes (HC-04 cells) and in mice.

Results

CYP3A activity was suppressed by 55% in mice 24 h after administration of mouse-adapted H1N1, while ˂10% activity remained in HC-04 cells after infection with H1N1 and H3N2 due to global suppression of cellular translation capacity, indicated by reduction (70%, H1N1, 56%, H3N2) of phosphorylated eukaryotic translation initiation factor 4e (eIF4E). AdEBO suppressed CYP3A activity in vivo (44%) and in vitro (26%) 24 hours after infection.

Conclusion

As the clinical evaluation of vaccines for SARS-CoV-2 and other global pathogens rise, studies to evaluate the impact of new vaccines and emerging pathogens on CYP3A4 and other metabolic enzymes are warranted to avoid therapeutic failures that could further compromise the public health during infectious disease emergencies.

KEYWORDS:

• Cytochrome P450 3A4
• drug metabolism
• ebola
• influenza
• liver
• vaccine

Acknowledgments

The authors thank Marcia Blackman (Trudeau Institute, Saranac Lake, NY) for the mouse-adapted PR8 influenza virus. We also thank Erica Ollmann Saphire and Marnie Fusco of the Scripps Research Institute for the generous donation of the recombinant Ebola glycoprotein production system for use in our studies. The HC-04 cells utilized in these studies were provided to the Malaria Research and Reference Reagent Resource Center (MR4) by Jetsumon Sattabongkot Prachumsri, Department of Entomology, USA Medical Component, Armed Forces Research Institute of Medical Science, Bangkok, Thailand. The authors also acknowledge the expert assistance of Stephen C. Schafer with artwork for the graphical abstract that accompanies this manuscript.

Contributions statement

K.J.S. participated in the design of experiments, data collection and analysis, and writing of the manuscript. R.G. participated in data analysis and writing of the manuscript. M.A.C. participated in the design of experiments, data analysis, and writing of the manuscript.

Declaration of interest

K Jonsson-Schmunk recieved a Continuing Fellowship from The University of Texas at Austin Graduate School. M Croyle has received the U01 Award from the National Institutes of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

CYP, cytochrome P450; PXR, pregnane X receptor; CAR, constitutive androstane receptor; RXRα, retinoid X receptor alpha; MOI, multiplicity of infection; (CEID50), chicken embryo infectious dose 50; SPF, specific pathogen free; qRT-PCR, quantitative real-time polymerase chain reaction; ERMBT, erythromycin breath test

Additional information

Funding

This work was supported by the National Institutes of Health NIAID Grant U01AI078045 (M.A.C.), a Special Research Grant from the Vice President of Research at The University of Texas at Austin (M.A.C.) and a Continuing Fellowship from The University of Texas at Austin Graduate School (K.J.S.).