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Enhanced toxicity for mice of 6-mercaptopurine with bacterial endotoxin
Abstract:
The toxicity of 6-mercaptopurine was potentiated by 2 mg of either Escherichia coli 026:B6 B endotoxin or Salmonella typhosa 0901 W endotoxin per kg. Nonlethal doses of heat-killed, gram-negative bacteria were also capable of potentiating the lethality of 6-mercaptopurine (6-MP). Salmonella minnesota S, the wild-type strain, and S. minnesota Re 595, a mutant containing only the lipid A and 2-keto-3-deoxyoctonate moiety of the endotoxin molecule, exhibited the same capability to enhance the toxic action of 6-MP. Endotoxin (lipopolysaccharide [LPS]) did not affect the clearance of 6-MP from the circulation, but did alter its apparent metabolism as indicated by blood levels of a metabolite, 6-thiouric acid. The concentration of blood urea nitrogen (BUN) in mice 18 h after injection of 100 mg of 6-MP per kg simultaneously with 2 mg of LPS per kg was significantly elevated over normal values. However, these BUN values were significantly less than those resulting from the administration of one mean lethal dose of either agent. The clearance from the circulation of the gram-negative organism E. coli HB, or the gram-positive organism Staphylococcus epidermidis S, was not affected by 6-MP. Endotoxin had no effect on the clearance of S. epidermidis S, but inhibited that of E. coli HB. When 6-MP and LPS were administered simultaneously with either bacterial species, only the clearance of E. coli HB was inhibited. Mice were protected from the lethality associated with combinations of 6-MP and LPS by (i) prior treatment with phenobarbital, (ii) caffeine, (iii) methylprednisolone, and (iv) polymyxin B sulfate. With the exception of caffeine, each regimen protected mice against the lethal effects of 400 mg of 6-MP per kg, and methylprednisolone or polymyxin B protected mice against 8 mg of LPS per kg.
Insights
Bacterial endotoxins, including lipopolysaccharide (LPS), significantly increase the toxicity of 6-mercaptopurine (6-MP). Several treatments, such as phenobarbital and methylprednisolone, can protect against these combined lethal effects.
Area of Science:
- Pharmacology and Toxicology
- Immunology
- Microbiology
Background:
- 6-Mercaptopurine (6-MP) is an immunosuppressive and chemotherapeutic agent.
- Bacterial endotoxins, particularly lipopolysaccharide (LPS) from Gram-negative bacteria, are potent immune stimulants.
- Interactions between chemotherapeutic agents and endotoxins can lead to unpredictable toxicological outcomes.
Purpose of the Study:
- To investigate the potentiation of 6-mercaptopurine toxicity by bacterial endotoxins.
- To examine the effects of combined 6-MP and endotoxin administration on bacterial clearance and host metabolism.
- To identify potential protective agents against the combined toxicity of 6-MP and LPS.
Main Methods:
- Mice were administered varying doses of 6-mercaptopurine (6-MP) and bacterial endotoxins (LPS) from Escherichia coli and Salmonella typhosa.
- The study assessed the lethality, 6-MP pharmacokinetics (clearance and metabolism), blood urea nitrogen (BUN) levels, and clearance of co-administered bacteria (E. coli and Staphylococcus epidermidis).
- Mice were pretreated with various agents (phenobarbital, caffeine, methylprednisolone, polymyxin B sulfate) to evaluate protective effects against combined 6-MP and LPS toxicity.
Main Results:
- Both Escherichia coli and Salmonella typhosa endotoxins potentiated the lethality of 6-MP in mice.
- Endotoxin did not alter 6-MP clearance but affected its metabolism, increasing 6-thiouric acid levels.
- Combined 6-MP and LPS administration elevated BUN levels, and endotoxin inhibited the clearance of E. coli but not S. epidermidis.
- Phenobarbital, methylprednisolone, and polymyxin B sulfate provided significant protection against the lethal effects of combined 6-MP and LPS.
Conclusions:
- Bacterial endotoxins significantly enhance the toxicity of 6-mercaptopurine, likely through altered metabolism rather than altered drug clearance.
- The combination of 6-MP and LPS impacts host defense mechanisms, as evidenced by altered bacterial clearance and elevated BUN.
- Pharmacological interventions, including methylprednisolone and polymyxin B, can mitigate the severe toxicity resulting from the co-administration of 6-MP and LPS.
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