Effect of streptozotocin-induced diabetes on tryptophan oxygenase activity and brain tryptophan levels in rats.

Alterations in brain tryptophan levels and the rate of hepatic tryptophan metabolism by tryptophan oxygenase (TPO) were studied in male Sprague-Dawley rats rendered diabetic by intravenous administration of streptozotocin (STZ), 65 mg/kg. Determinations were made at the early onset of diabetes (1-4 days of glucosuria) and 8-12 days following STZ injection. Rats were considered diabetic if their serum glucose exceeded 250 mg percent. Tryptophan brain levels decreased by 17% after four days of diabetes, decreased by 22% on day 5, and by 27% 8-12 days after STZ. Brain 5-hydroxyindoleacetic acid levels were significantly decreased by 27% on day 5, but returned to control levels by 8-12 days. Serotonin concentration in the brain remained at control values. The initial appearance of a significant increase in total TPO activity coincided with the onset of a change in brain tryptophan. Total TPO activity increased by 60% after 4 days of diabetes. The increase was caused by an increase in apoenzyme activity since holoenzyme activity remained unaltered. Holoenzyme activity was increased by 37% after 8-12 days, and accounted for the change in total TPO activity. Insulin treatment reversed the STZ-induced alterations. The results are compatible with the hypothesis that diabetes increases hepatic TPO activity that in turn results in decreased plasma tryptophan levels and decreased availability of tryptophan for brain uptake. However, compensatory changes appear to maintain a stable serotonin concentration in the brain. The early and later changes in TPO activity during diabetes are apparently caused by different regulatory events.