Membrane action of chloramphenicol measured by protozoan motility inhibition.
The mechanism of the grey baby syndrome produced by chloramphenicol overdose is poorly understood. The present study assessed the membrane toxicity of this agent by means of its depressant effect on excitable tissues. The inhibition by drugs of protozoan motility was used as a toxicity endpoint, measured by the swimming speed of Tetrahymena pyriformis using an image analysis system. The n-octanol/water partition coefficient at pH 7.4, 37 degrees C was determined as a measure of the hydrophobicity of the drugs. Chloramphenicol dose-dependently depressed the motility of the test organism with an IC50 value (the concentration reducing the mean swimming speed to 50% of control) of 2.95 +/- 0.25 mM, in contrast to a significantly weaker effect of its succinate salt with an IC50 of 28.2 +/- 1.93 mM. Thiamphenicol, a drug with similar properties to chloramphenicol, produced little effect on protozoan motility. Several other antibiotics either in free or salt forms were also ineffective. A series of agents known to possess membrane stabilising action also tested for comparison showed that chloramphenicol possesses the ability to reduce protozoan motility. Measurement of the n-octanol/water partition coefficient revealed a value for chloramphenicol of 11.9 +/- 0.66. This property was correlated with protozoan immobilising potency among a series of heterogeneous compounds, suggesting that the mechanism involved a hydrophobic interaction with the excitable membrane. These results show that chloramphenicol has a depressant effect on protozoan motility comparable to agents with known toxicity effects on cell membranes. This suggests that chloramphenicol has the potential to cause membrane-mediated toxic effects, a mode of action that may underlie its acute toxicity to excitable tissues.
Wu
C
C
Medical Toxicology Unit, Guy's Hospital, London, UK.
Clift
P
P
Fry
C H
CH
Henry
J A
JA
D020003:1-Octanol; D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D002701:Chloramphenicol / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D007928:Lethal Dose 50; D009068:Movement / Q000187:drug effects; D000442:Octanols / Q000737:chemistry; D011500:Protein Synthesis Inhibitors / Q000633:toxicity*; D012015:Reference Standards; D013769:Tetrahymena pyriformis / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014867:Water / Q000737:chemistry
D000900:Anti-Bacterial Agents; D000442:Octanols; D011500:Protein Synthesis Inhibitors; D014867:Water; D002701:Chloramphenicol; D020003:1-Octanol