Gentamicin-induced hearing loss: A retrospective study using the Food and Drug Administration Adverse Event Reporting System and a toxicological study using drug-gene network analysis

Mizuki Tanaka; Kiyoka Matsumoto; Riko Satake; Yu Yoshida; Misaki Inoue; Shiori Hasegawa; Takaaki Suzuki; Mari Iwata; Kazuhiro Iguchi; Mitsuhiro Nakamura

doi:10.1016/j.heliyon.2021.e07429

Gentamicin-induced hearing loss: A retrospective study using the Food and Drug Administration Adverse Event Reporting System and a toxicological study using drug-gene network analysis

Heliyon. 2021 Jun 29;7(7):e07429. doi: 10.1016/j.heliyon.2021.e07429. eCollection 2021 Jul.

Authors

Mizuki Tanaka¹, Kiyoka Matsumoto¹, Riko Satake¹, Yu Yoshida¹, Misaki Inoue¹, Shiori Hasegawa^{1

2}, Takaaki Suzuki^{1

3}, Mari Iwata⁴, Kazuhiro Iguchi⁵, Mitsuhiro Nakamura¹

Affiliations

¹ Laboratory of Drug Informatics, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, 501-1196, Japan.
² Department of Pharmacy, Kobe City Medical Center General Hospital, 2-1-1 Minatojima Minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
³ Gifu Prefectural Government, 2-1-1 Yabutaminami, Gifu, 500-8570, Japan.
⁴ Kifune Pharmacy, 2-23-2 Hasuike, Yanaizu-cho, Gifu, 501-6103, Japan.
⁵ Laboratory of Community Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-Nishi, Gifu, 501-1196, Japan.

Abstract

The objectives of the study were to evaluate the relationship between gentamicin (GEN) and hearing loss using the Food and Drug Administration Adverse Event Reporting system (FAERS) database and elucidate the potential toxicological mechanism of GEN-induced hearing loss through a drug-gene network analysis. Using the preferred terms and standardized queries from the Medical Dictionary for Regulatory Activities, we calculated the reporting odds ratios (RORs). We extracted GEN-associated genes (seed genes) and analyzed drug-gene interactions using the ClueGO plug-in in the Cytoscape software and the DIseAse MOdule Detection (DIAMOnD) algorithm. The lower limit of the 95% confidence interval (CI) of the ROR for aminoglycosides (AG) antibacterials was over 1, and the ROR was 5.5 (5.1-6.0). We retrieved 17 seed genes related to GEN from the PharmGKB and Drug Gene Interaction databases. In total, 1018 human genes interacting with GEN were investigated using ClueGO. Through Molecular Complex Detection (MCODE) analysis, we identified 17 local gene clusters. The nodes and edges of the highest-ranked local gene cluster named "Cluster 1" were 30 and 433, respectively. According to the ClueGO analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Cluster 1 genes were highly enriched in "oxidative phosphorylation." According to the ClueGO analysis using ClinVar, Cluster 1 genes were highly enriched in "mitochondrial diseases," "mitochondrial complex I deficiency," "hereditary hearing loss and deafness," and "Leigh syndrome." We identified 60 GEN-associated genes using the DIAMOnD algorithm. Several GEN-associated genes in the DIAMOnD algorithm were highly enriched in "PI3K-Akt signaling pathway," "Ras signaling pathway," "focal adhesion," "MAPK signaling pathway," "regulation of actin cytoskeleton," "oxidative phosphorylation," and "ECM-receptor interaction." Our analysis demonstrated an association between several AGs and hearing loss using the FAERS database. Drug-gene network analysis demonstrated that GEN may be associated with oxidative phosphorylation-associated genes and integrin genes, which may be associated with hearing loss.

Keywords: Aminoglycoside; Food and Drug Administration Adverse Event Reporting System; Gentamicin; Hearing loss; Integrin; Oxidative phosphorylation; Protein−protein interaction.