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Effect of polymyxin B on hemoglobin-mediated hepatotoxicity
Abstract:
In previous studies, enhanced toxicity of hemoglobin when combined with endotoxin has suggested a specific binding site. This binding may take place even when endotoxin-free hemoglobin is administered, due to some low levels of endotoxin usually present in the portal vein. To test this hypothesis, we administered endotoxin-free, stroma-free human hemoglobin (SFH) to rabbits in doses shown previously to be hepatotoxic or lethal. A second group of rabbits received the anti-endotoxin antibiotic polymyxin B (PB) to inactivate endotoxin, followed by a dose of SFH. A control group received intravenous PB alone. There was no differences in the incidence of hepatotoxicity among these three groups. To show the binding interactions of endotoxin with PB and endotoxin with hemoglobin, an experiment using toluidine blue was performed. According to this study, specific binding of hemoglobin with endotoxin did not occur. Our results do not agree with previous suggestions that hemoglobin-mediated hepatotoxicity is due to the interaction in vivo of hemoglobin with low levels of endogenous endotoxin.
Insights
Hemoglobin-induced liver damage is not caused by binding with endotoxin. Studies show endotoxin-free hemoglobin (SFH) and polymyxin B (PB) did not alter hepatotoxicity, refuting prior hypotheses.
Area of Science:
- Biochemistry
- Toxicology
- Hepatology
Background:
- Previous studies suggested hemoglobin-endotoxin binding causes liver toxicity.
- This binding was hypothesized to occur even with low endotoxin levels in portal circulation.
Purpose of the Study:
- To investigate the hypothesis that hemoglobin-mediated hepatotoxicity results from in vivo interaction with endogenous endotoxin.
- To determine if endotoxin-free hemoglobin (SFH) administration causes hepatotoxicity in rabbits, with or without endotoxin inactivation.
Main Methods:
- Administered endotoxin-free SFH to rabbits.
- Administered SFH with polymyxin B (PB), an anti-endotoxin antibiotic, to a second group.
- A control group received PB alone.
- Utilized toluidine blue assay to assess binding interactions.
Main Results:
- No significant difference in hepatotoxicity incidence was observed among the three groups.
- The toluidine blue experiment indicated no specific binding between hemoglobin and endotoxin.
- Results contradict previous suggestions of hemoglobin-endotoxin interaction driving hepatotoxicity.
Conclusions:
- Hemoglobin-mediated hepatotoxicity is unlikely to be caused by in vivo interaction with low levels of endogenous endotoxin.
- The study refutes the proposed binding mechanism between hemoglobin and endotoxin in the context of liver toxicity.