Evaluation of the cytotoxic effects of bis-quaternary ammonium antimicrobial reagents on human cells.
The cytotoxic effects of newly synthesized bis-quaternary ammonium compounds (bis-QACs) and benzalkonium chloride were investigated on skin and blood cells, namely normal human epidermal keratinocytes of neonatal foreskin, a normal human skin fibroblast cell line NB1RGB, erythrocytes and a lymphoma cell line JM. The bis-QACs tested were 4, 4'-(1,6-hexamethylenedithio)bis(1-octylpyridinium iodide) (4DTBP-6, 8), N,N'-tetramethylenebis(1-dodecyl-4-carbamoylpyridinium iodide) (4BCAP-4,12), N,N'-hexamethylenebis(1-decyl-4-carbamoylpyridinium iodide) (4BCAP-6,10), 4,4'-(1,4-tetramethylenedicarbonyldiamine) bis (1-decylpyridinium iodide) (4DCABP-4,10), 4,4'-(1, 4-tetramethylenedicarbonyldiamine) bis (1-dodecylpyridinium iodide) (4DCABP-4,12), 4,4'-(1, 4-phenyldicarbonyldiamine)bis(1-dodecylpyridinium iodide) (4DCABP-P, 12), and 4,4'-(1, 6-hexamethylenedioxydicarbonyl)bis(1-dodecylpyridinium iodide) (4DOCBP-6,12). All bis-QACs consisted of two identical alkylpyridinium rings and bridge structure linking rings to each other have a methylene bridge but only 4DCABP-P,12 has a phenyl ring as a bridge. Most of the LD(50) values in acute cytotoxic assays of these bis-QACs tended to be lower than those of benzalkonium chloride. However, the comparison of the antibacterial activity against cytotoxic effects on several human cells revealed that bis-QACs, especially 4DTBP-6,8, have wide concentration ranges showing sufficient antibacterial activity and lower cytotoxic effect on human cells (except for 4DOCBP-6,12), although benzalkonium chloride caused significant human cell damage at the concentrations necessary for antibacterial activity. Moreover, judging from the LD(50) value of 4DTBP-6,8 [67 microM, a 6.7-fold higher concentration than the upper value of MIC] obtained in an artificial human skin model TESTSKIN, 4DTBP-6,8 is thought to be a more effective and safer antiseptic reagent for application to the skin surface than benzalkonium chloride. Taken together, bis-QACs are expected to be a promising new generation of antimicrobial QACs.
Nagamune
H
H
Department of Biological Science and Technology, Faculty of Engineering, The University of Tokushima, #1, 2-chome, Minami-josanjima cho, Tokushima, Japan.
Maeda
T
T
Ohkura
K
K
Yamamoto
K
K
Nakajima
M
M
Kourai
H
H
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000633:toxicity*; D001419:Bacteria / Q000187:drug effects; D001548:Benzalkonium Compounds / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D005347:Fibroblasts; D006801:Humans; D007202:Indicators and Reagents; D015603:Keratinocytes / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects; D016399:Lymphoma, T-Cell / Q000473:pathology; D008826:Microbial Sensitivity Tests; D011310:Preservatives, Pharmaceutical / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000633:toxicity*
D000900:Anti-Bacterial Agents; D001548:Benzalkonium Compounds; D007202:Indicators and Reagents; D011310:Preservatives, Pharmaceutical; D000644:Quaternary Ammonium Compounds