Linezolid-Induced Thrombocytopenia Is Caused by Suppression of Platelet Production via Phosphorylation of Myosin Light Chain 2

• Published in: Biological & pharmaceutical bulletin Vol. 39; no. 11; pp. 1846 - 1851
• Main Authors: Tajima, Masataka, Kato, Yoshinori, Matsumoto, Jun, Hirosawa, Iori, Suzuki, Mariko, Takashio, Yuki, Yamamoto, Mao, Nishi, Yoshifumi, Yamada, Harumi
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 2016; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: adverse effect; Animals; Anti-Bacterial Agents - adverse effects; Antibiotic resistance; Biotechnology; Blood Platelets - drug effects; Blood Platelets - metabolism; Cardiac Myosins - metabolism; Cell Differentiation - drug effects; Cell Line; Cell Line, Tumor; Cell lines; Cell proliferation; Cell Proliferation - drug effects; Cytotoxicity; Drug resistance; Erythroleukemia; Humans; L-Lactate dehydrogenase; L-Lactate Dehydrogenase - metabolism; Lactic acid; Light levels; Linezolid; Linezolid - adverse effects; Liver; Liver diseases; Male; mechanism; Megakaryocytes; Methicillin; Myosin; myosin light chain; Myosin Light Chains - metabolism; Pathogenesis; Phosphorylation; Phosphorylation - drug effects; Platelets; Rats, Wistar; Renal function; Risk factors; Rodents; Side effects; Staphylococcus aureus; Staphylococcus infections; Thrombocytopenia; Thrombocytopenia - chemically induced; Thrombocytopenia - metabolism; Vancomycin
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b16-00427

Linezolid (LZD) is an antimicrobial that is commonly used for treatment of vancomycin-resistant Enterococci and methicillin-resistant Staphylococcus aureus infections. However, the development of thrombocytopenia, one of the most frequent adverse side effects of this antimicrobial, can lead to discontinuation of LZD treatment. While clinical studies indicate that risk factors for the development of LZD-induced thrombocytopenia include treatment for >14 consecutive days, renal dysfunction, and chronic liver disease, the fundamental mechanism governing the pathogenesis of this disorder remains unclear. In this study, we aimed to elucidate the mechanism of LZD-induced thrombocytopenia by investigating the impact of LZD treatment on platelet destruction and production using rat platelet-rich plasma (PRP) and human immortalized cell lines, respectively. Compared to the control population, an increase in lactate dehydrogenase release was not detected upon exposure of rat PRP to varying concentrations of LZD, indicating that this compound is not cytotoxic towards platelets. Meanwhile, LZD treatment resulted in a significant dose-dependent increase in the proliferation of HEL human erythroleukemia and MEG-01 human megakaryoblast cells in vitro, but did not influence the differentiation of these cell lines. Lastly, LZD treatment yielded elevated levels of phosphorylation of myosin light chain 2 (MLC2), which regulates platelet release, in MEG-01 cells. Based on these results, we speculate that LZD induces thrombocytopenia by promoting MLC2 phosphorylation and thereby suppressing the release of platelets from mature megakaryocytes. These findings provide the first insight into the mechanism of LZD-mediated thrombocytopenia and may facilitate the development of strategies to treat and/or prevent this disease.