Contribution of aldehyde oxidase to methotrexate-induced hepatotoxicity: in vitro and pharmacoepidemiological approaches

ABSTRACT

Background

Methotrexate (MTX) is partially metabolized by aldehyde oxidase (AOX) in the liver and its clinical impact remains unclear. In this study, we aimed to demonstrate how AOX contributes to MTX-induced hepatotoxicity in vitro and clarify the relationship between concomitant AOX inhibitor use and MTX-associated liver injury development using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).

Methods

We assessed intracellular MTX accumulation and cytotoxicity using HepG2 cells. We used the FAERS database to detect reporting odds ratio (ROR)-based MTX-related hepatotoxicity event signals.

Results

AOX inhibition by AOX inhibitor raloxifene and siRNA increased the MTX accumulation in HepG2 cells and enhanced the MTX-induced cell viability reduction. In the FAERS analysis, the ROR for MTX-related hepatotoxicity increased with non-overlap of 95% confidence interval when co-administered with drugs with higher I_{max, u} (maximum unbound plasma concentration)/IC₅₀ (half-maximal inhibitory concentration for inhibition of AOX) calculated based on reported pharmacokinetic data.

Conclusion

AOX inhibition contributed to MTX accumulation in the liver, resulting in increased hepatotoxicity. Our study raises concerns regarding MTX-related hepatotoxicity when co-administered with drugs that possibly inhibit AOX activity at clinical concentrations.

KEYWORDS:

• Aldehyde oxidase
• drug-drug interaction
• FAERS
• liver injury
• methotrexate

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Authors’ contributions

Study design: A Moriyama, K Narumi, and M Kobayashi. Experiments and data analysis: A Moriyama, H Ueda, K Narumi, and S Asano. Writing original draft: K Narumi. All the authors have reviewed and approved the final version of the manuscript.

Data availability statement

The datasets generated and/or analyzed during the current study are available in the FAERS repository (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).

Acknowledgments

We thank Editage (http://www.editage.jp) for English language editing.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2024.2352453

Additional information

Funding

This study was funded by the Japan Society for the Promotion of Science, KAKENHI [grant number JP23K06229 to KN].