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Altered distribution and toxicity of digitoxigenin in fasted mice
Abstract:
Intravenous administration of digitoxigenin (DTXGN) evokes seizure episodes in mice which may be dependent on brain biogenic amines such as serotonin (5-HT). Fasting is known to have effects on both drug toxicity and brain 5-HT synthesis. The purpose of this study was to assess the effects of overnight fasting on DTXGN toxicity. The i.v. LD-50 of DTXGN was increased by 61% in fasted mice. Adjustment of DTXGN dose for the decrease in body weight of fasted mice did not alter the fasting induced protection. A loading dose of 1-tryptophan (25 mg/kg, i.p.) did not alter mortality rates in either fed or fasted mice. Cortical levels of 3H-DTXGN were decreased significantly by 25% in fasted mice. Liver and blood levels were elevated significantly. These data suggest that decreased DTXGN toxicity is associated with a decrease in its distribution to the cerebral cortex and emphasize the importance of acute dietary status in the expression of drug toxicity.
Insights
Overnight fasting significantly reduces digitoxigenin (DTXGN) toxicity in mice by 61%. This protective effect is linked to decreased DTXGN distribution to the brain, highlighting diet
Area of Science:
- Neuropharmacology
- Toxicology
- Nutritional Science
Background:
- Intravenous digitoxigenin (DTXGN) can induce seizures in mice, potentially mediated by brain biogenic amines like serotonin (5-HT).
- Fasting is known to influence drug toxicity and central nervous system serotonin synthesis.
Purpose of the Study:
- To investigate the impact of overnight fasting on the toxicity of digitoxigenin (DTXGN).
- To determine if fasting alters DTXGN distribution within the body, particularly in the brain.
Main Methods:
- Determined the intravenous LD-50 of DTXGN in fasted versus fed mice.
- Administered 1-tryptophan to assess its effect on DTXGN toxicity in both groups.
- Measured cortical, liver, and blood levels of radiolabeled DTXGN (3H-DTXGN) in fasted and fed mice.
Main Results:
- Fasting increased the i.v. LD-50 of DTXGN by 61%.
- This protection persisted even after adjusting DTXGN dose for body weight reduction in fasted mice.
- Cortical levels of 3H-DTXGN were reduced by 25% in fasted mice, while liver and blood levels were significantly elevated.
Conclusions:
- Overnight fasting confers significant protection against DTXGN toxicity.
- Reduced DTXGN toxicity in fasted mice is associated with decreased distribution to the cerebral cortex.
- Acute dietary status critically influences the expression of drug toxicity, particularly for compounds affecting the central nervous system.