Anestesia e Pesquisa Clínica
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Local Anesthetics with High Lipophilicity are Toxic, While Local Anesthetics with Low pka Induce More Apoptosis in Human Leukemia Cells

Shin Onizuka, Tetsu Yonaha and Isao Tsuneyoshi

Many studies have indicated that local anesthetics are cytotoxic and can induce apoptosis; however, the types of local anesthetics and the induction rates of apoptosis remain unclear. The aim of this study was to clarify the local anesthetics that induce apoptosis or necrosis and their induction-related factors.

Methods: Lidocaine, mepivacaine, bupivacaine, ropivacaine, tetracaine, dibucaine, procaine, and QX-314 were evaluated for apoptosis and necrosis in HL-60 human leukemia cell lines. Apoptosis and necrosis were analyzed by double-staining assay with propidium iodide (PI) and annexin-V and were measured by flow cytometry (FACS). DNA fragmentation was used for the analysis of apoptosis.

Results: In the double-staining assay by flow cytometry, drugs with high lipophilicity were most cytotoxic. The comparative LD50 values were dibucaine > tetracaine > bupivacaine > ropivacaine > mepivacaine > lidocaine > procaine > QX-314. The LD50 were correlated with lipophilicity (logP). The comparative maximum rates of annexin-positive and PInegative apoptotic cells were lidocaine > mepivacaine > ropivacaine > bupivacaine > procaine > tetracaine > dibucaine > QX314 and were correlated with pKa. Lidocaine and mepivacaine significantly induced DNA fragmentation. DNA fragmentation was also correlated with pKa.

Conclusion: The results indicate that local anesthetics with high lipophilicity are highly toxic and induce mainly necrosis, while local anesthetics with low pKa induce more apoptosis.