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Mechanism of histamine release induced by levofloxacin, a fluoroquinolone antibacterial agent
1Drug Safety Research Laboratory, Daiichi Pharmaceutical Co., Ltd., 16-13 Kitakasai 1-chome, Edogawa-ku, Tokyo, Japan. morikslf@daiichipharm.co.jp
Abstract:
The present study was designed to clarify the mechanism of histamine release caused by levofloxacin, a fluoroquinolone antibacterial agent, using rat peritoneal mast cells. Levofloxacin induced a concentration-dependent histamine secretion from 300 microg/ml without lactate dehydrogenase leakage, and the release was rapidly completed within 30 s. This action was dependent on temperature, energy, pH and intracellular Ca(2+), similarly to the effect of compound 48/80, a basic compound. Unlike that with the calcium ionophore A23187, histamine secretion due to levofloxacin or compound 48/80 was prevented by pretreatment with either pertussis toxin or benzalkonium chloride, a selective inhibitor of G proteins of G(i) subtypes. Moreover, the histamine release elicited by levofloxacin or compound 48/80 was suppressed by hydrolysis of sialic acid residues on the cell surface brought about by neuraminidase. These results demonstrate that the mechanism by which levofloxacin exerts histamine release may be closely linked to activation of pertussis toxin-sensitive G proteins.
Insights
Levofloxacin triggers histamine release from mast cells via a mechanism involving pertussis toxin-sensitive G proteins. This process is rapid, concentration-dependent, and requires cellular energy and calcium, but does not cause cell damage.
Area of Science:
- Pharmacology
- Cell Biology
- Immunology
Background:
- Levofloxacin is a fluoroquinolone antibiotic.
- Antibiotics can sometimes cause adverse reactions, including histamine release.
- The precise mechanism of levofloxacin-induced histamine release is not fully understood.
Purpose of the Study:
- To elucidate the cellular and molecular mechanisms underlying histamine release induced by levofloxacin.
- To investigate the role of G proteins and cell surface molecules in this process.
Main Methods:
- Experiments were conducted using rat peritoneal mast cells.
- Histamine release was measured in response to varying concentrations of levofloxacin.
- Cell viability was assessed using lactate dehydrogenase leakage assays.
- The involvement of temperature, energy, pH, intracellular calcium, G proteins (pertussis toxin, benzalkonium chloride), and sialic acid residues (neuraminidase) was investigated.
Main Results:
- Levofloxacin induced concentration-dependent histamine secretion starting at 300 microg/ml without causing cell lysis.
- Histamine release was rapid (within 30 s) and dependent on temperature, energy, pH, and intracellular Ca(2+).
- The release was inhibited by pertussis toxin and benzalkonium chloride, suggesting G protein involvement (G(i) subtypes).
- Neuraminidase treatment, which hydrolyzes sialic acid residues, also suppressed levofloxacin-induced histamine release.
Conclusions:
- Levofloxacin-induced histamine release from mast cells is a rapid, energy-dependent process.
- The mechanism is closely linked to the activation of pertussis toxin-sensitive G proteins.
- Cell surface sialic acid residues may play a role in mediating this response.