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Kirkland, David J.; Sheil, Meredith L.; Streicker, Michael A.; Johnson, George E.
Regulatory toxicology and pharmacology, February 2021, 2021-Feb, 2021-02-00, Letnik: 119Journal Article
Lidocaine has not been associated with cancer in humans despite 8 decades of therapeutic use. Its metabolite, 2,6-xylidine, is a rat carcinogen, believed to induce genotoxicity via N-hydroxylation and DNA adduct formation, a non-threshold mechanism of action. To better understand this dichotomy, we review literature pertaining to metabolic activation and genotoxicity of 2,6-xylidine, identifying that it appears resistant to N-hydroxylation and instead metabolises almost exclusively to DMAP (an aminophenol). At high exposures (sufficient to saturate phase 2 metabolism), this may undergo metabolic threshold-dependent activation to a quinone-imine with potential to redox cycle producing ROS, inducing cytotoxicity and genotoxicity. A new rat study found no evidence of genotoxicity in vivo based on micronuclei in bone marrow, comets in nasal tissue or female liver, despite high level exposure to 2,6-xylidine (including metabolites). In male liver, weak dose-related comet increases, within the historical control range, were associated with metabolic overload and acute systemic toxicity. Benchmark dose analysis confirmed a non-linear dose response. The weight of evidence indicates 2,6-xylidine is a non-direct acting (metabolic threshold-dependent) genotoxin, and is not genotoxic in vivo in rats in the absence of acute systemic toxic effects, which occur at levels 35 × beyond lidocaine-related exposure in humans. •Lidocaine metabolite 2,6-xylidine primarily metabolises via an amino-phenol pathway.•Published studies show variable genotoxicity consistent with cytotoxic/ROS-related effects.•A new rat study was negative for bone marrow MN, nasal tissue and female liver comets.•At MTD there was a metabolic overload threshold with low rise in male liver comets.•2,6-xylidine is not genotoxic in vivo in the absence of acute systemic toxicity.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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