Chronic Toxoplasma infection affects gene expression of drug-metabolizing enzymes in mouse liver

Abstract

1. Toxoplasma gondii is an intracellular protozoan parasite causing toxoplasmosis, an infectious disease affecting warm-blooded vertebrates worldwide. Many drug-metabolizing enzymes are located in the liver, a major organ of drug metabolism, and their function can be affected by pathogen infection.

2. Using next-generation sequencing (RNA-seq) and quantitative polymerase chain reaction (qPCR), changes in the hepatic expressions of drug-metabolizing enzymes were analysed in mice chronically infected with T. gondii. The analysis found that, among drug-metabolizing enzymes, 22 genes were upregulated and 28 genes were downregulated (≥1.5-fold); of these 5 and 17 genes, respectively, were cytochromes P450 (Cyp or P450).

3. Subsequent qPCR analysis showed that six P450 genes were upregulated significantly (≥1.5-fold, p < 0.05), namely, Cyp1b1, Cyp2c29, Cyp2c65, Cyp2d9, Cyp2d12, and Cyp3a59, whereas nine P450 genes were downregulated significantly (≥1.5-fold, p < 0.05), namely, Cyp2c38, Cyp2c39, Cyp2c44, Cyp2c69, Cyp2d40, Cyp2e1, Cyp3a11, Cyp3a41, and Cyp3a44.

4. Moreover, metabolic assays in infected mouse liver using typical P450 substrates revealed that midazolam 1′-hydroxylation and testosterone 2-hydroxylation activities decreased significantly (≥1.5-fold, p < 0.05), whereas testosterone 16-hydroxylation activity increased significantly (≥1.5-fold, p < 0.05).

5. Chronic Toxoplasma infection affects drug metabolism, at least partly, by altering the gene expressions of drug-metabolizing enzymes, including P450s.

Keywords:

• Cytochrome P450
• drug-metabolizing enzymes
• mouse liver
• RNA-seq
• Toxoplasma infection

Acknowledgement

We thank Norie Murayama for technical assistance and David Smallbones for copyediting a draft of this article.

Disclosure statement

The authors report no declarations of interest.

Data availability statement

All data generated or analysed during this study are included in this published article.

Additional information

Funding

This work was supported partly by the Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research 20K06434 and 23K05538].