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Role of tryptophan pyrrolase in endotoxin poisoning
Abstract:
Using substrate induction as a tool, we attempted to determine the role of tryptophan pyrrolase in the response to endotoxin in mice. Previous results have shown that the administration of the ld(50) of endotoxin lowers tryptophan pyrrolase activity. alpha-Methyltryptophan was found to maintain tryptophan pyrrolase activity above control levels in endotoxin-poisoned mice without increasing survival. 5-Hydroxytryptophan, by contrast, lowered tryptophan pyrrolase activity but did not sensitize mice to endotoxin. These results suggest that tryptophan pyrrolase per se does not play a unique role in survival of mice poisoned with endotoxin. This enzyme, however, may reflect the fate of other liver enzymes inducible by adrenocorticoids. In mice given concurrent injections of tryptophan and endotoxin, tryptophan pyrrolase activity was elevated to a level intermediate between that of normal mice and that of mice given tryptophan alone. The mice injected with tryptophan and endotoxin also had about the same mortality as mice given endotoxin alone. Mice treated with tryptophan 4 hr after endotoxin, at a time when the substrate did not fully elevate tryptophan pyrrolase activity, died convulsively and in larger numbers than those given endotoxin alone. This effect was reversed by prior treatment with cyproheptadine, an antiserotonin drug. These results indicate that the depression of tryptophan pyrrolase activity previously observed in vitro after injection of endotoxin reflects an actual decrease in the in vivo activity of the enzyme.
Insights
Tryptophan pyrrolase activity is decreased by endotoxin in mice, but this enzyme does not directly impact survival. Late tryptophan administration, however, increases mortality, suggesting a complex role in endotoxin response.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Endotoxin administration is known to decrease tryptophan pyrrolase activity in mice.
- The precise role of tryptophan pyrrolase in the physiological response to endotoxin remains unclear.
Purpose of the Study:
- To investigate the role of tryptophan pyrrolase in endotoxin-induced responses in mice.
- To determine if modulating tryptophan pyrrolase activity affects survival rates in endotoxin-poisoned mice.
Main Methods:
- Utilizing substrate induction to manipulate tryptophan pyrrolase activity.
- Administering endotoxin and various tryptophan analogs (alpha-Methyltryptophan, 5-Hydroxytryptophan) to mice.
- Assessing tryptophan pyrrolase activity, survival rates, and mortality following endotoxin challenge.
- Investigating the effect of late tryptophan administration and concurrent cyproheptadine treatment.
Main Results:
- alpha-Methyltryptophan maintained enzyme activity but did not improve survival.
- 5-Hydroxytryptophan lowered enzyme activity without increasing endotoxin sensitivity.
- Concurrent tryptophan and endotoxin administration resulted in intermediate enzyme activity and similar mortality to endotoxin alone.
- Late tryptophan administration (4 hours post-endotoxin) increased mortality, an effect reversed by cyproheptadine.
Conclusions:
- Tryptophan pyrrolase activity itself does not appear to be a critical determinant of survival in endotoxin-poisoned mice.
- The observed decrease in enzyme activity post-endotoxin reflects a genuine in vivo reduction.
- The timing of tryptophan administration significantly influences the outcome, suggesting indirect roles and potential interactions with serotonin pathways.