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Author Notes:

Correspondence: etmorga@emory.edu; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA 30322, USA

Edward T. Morgan ORCID: https://orcid.org/0000-0003-4273-2261

Tracey J. Lamb and Edward T. Morgan are joint senior authors.

SMM, CL, KHL, PNM, BAN, DPJ, TJL and ETM conceptualized the study and participated in research design; SMM, CL, KHL, PNM and BAN conducted the experiments; SMM, KHL, PNM, RDH, TJM, TJL and ETM performed data analyses; SMM, CL, KHL, PNM, RDH, TJM, BAN, DPJ, TJL and ETM wrote or contributed to the writing of the manuscript. All authors read and approved the final manuscript.

The authors declare that they have no competing interests.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health [Grant Number R01DK0723721].

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Infectious Diseases
  • Parasitology
  • Tropical Medicine
  • Plasmodium chabaudi chabaudi
  • Drug metabolism
  • Cytochrome P450
  • Liver
  • Gene expression
  • IN-VITRO METABOLISM
  • HUMAN LIVER-MICROSOMES
  • PREGNANE-X-RECEPTOR
  • HEPATIC CYTOCHROME-P450
  • FALCIPARUM-MALARIA
  • PLASMODIUM-BERGHEI
  • GENE-REGULATION
  • QUININE
  • PHARMACOKINETICS
  • IDENTIFICATION

A non-lethal malarial infection results in reduced drug metabolizing enzyme expression and drug clearance in mice

Journal Title:

Malaria Journal

Volume:

Volume 18, Number 1

Publisher:

, Pages 234-234

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Given the central importance of anti-malarial drugs in the treatment of malaria, there is a need to understand the effect of Plasmodium infection on the broad spectrum of drug metabolizing enzymes. Previous studies have shown reduced clearance of quinine, a treatment for Plasmodium infection, in individuals with malaria. Methods: The hepatic expression of a large panel of drug metabolizing enzymes was studied in the livers of mice infected with the AS strain of Plasmodium chabaudi chabaudi, a nonlethal parasite in most strains of mice with several features that model human Plasmodium infections. C57BL/6J mice were infected with P. chabaudi by intraperitoneal injection of infected erythrocytes and sacrificed at different times after infection. Relative hepatic mRNA levels of various drug metabolizing enzymes, cytokines and acute phase proteins were measured by reverse transcriptase-real time PCR. Relative levels of cytochrome P450 proteins were measured by Western blotting with IR-dye labelled antibodies. Pharmacokinetics of 5 prototypic cytochrome P450 substrate drugs were measured by cassette dosing and high-resolution liquid chromatography-mass spectrometry. The results were analysed by MANOVA and post hoc univariate analysis of variance. Results: The great majority of enzyme mRNAs were down-regulated, with the greatest effects occurring at the peak of parasitaemia 8 days post infection. Protein levels of cytochrome P450 enzymes in the Cyp 2b, 2c, 2d, 2e, 3a and 4a subfamilies were also down-regulated. Several distinct groups differing in their temporal patterns of regulation were identified. The cassette dosing study revealed that at the peak of parasitaemia, the clearances of caffeine, bupropion, tolbutamide and midazolam were markedly reduced by 60-70%. Conclusions: These findings in a model of uncomplicated human malaria suggest that changes in drug clearance in this condition may be of sufficient magnitude to cause significant alterations in exposure and response of anti-malarial drugs and co-medications.

Copyright information:

© 2019 The Author(s).

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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