Kosmetische Medizin 6-2011: 295-299

Keratinocyte cytoxicity of muscle relaxant chlormezanone and its metabolites in vitro

UWE WOLLINA, UTA-CHRISTINA HIPLER, ANDREAS SEELING, AND HERBERT OELSCHLÄGER

KEY WORDS: Chlormezanone, cytotoxicity, HaCaT keratinocytes

SUMMARY:
Chlormezanone [2-(4-Chlorphenyl)-3-methyl-3,4,5,6-tetrahydro-2H-1,3-thiazin-4-on-1,1-dioxide] is a centrally acting muscle relaxant. The drug had been discussed as a possible cause of severe cutaneous side effects such as Lyell’s syndrome. The reasons for the induction of Lyell’s disease have not been fully understood. We evaluated possible cytotoxic effects on keratinocytes in an in vitro model. We investigated chlormezanone, enantiomers and metabolites obtained by preparative high pressure liquid chromatography.

The metabolites used herein were 4-chloro benzyl alcohol (S1); 4-chlorobenzyl aldehyde (S2), 4-chloro benzoic acid (S3), and 4-chlorohippuric acid (S4). Human epidermal keratinocytes of the immortal non-malignant HaCaT cell line were employed. We used an ultrasensitive fluorescent nucleic acid stain to quantify double-stranded (ds) DNA related to the cell count. In addition, an ATP bioluminescence assay was used to quantify viable cell number. Only the highest concentration of chlormezanone used herein showed a significant reduction of ATP levels. The racemate was more efficient than both enatiomers. In contrast to the other metabolites, S2 showed a significant dose-dependent cytotoxicity in the whole concentration range after 48 h. These findings indicate that variations in metabolism of chlormezanone might result in a variable cytotoxicity exerted by the racemate and its enantiomers and the metabolite 4-chlorobenzyl aldehyde (S2) but not other metabolites investigated.

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