Inhibition of tryptophan-pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats

ABSTRACT

To investigate in-vitro as well as in-vivo effects of various doses of fluoxetine [SSRI] on tryptophan metabolism in rats. Design: A pre-clinical study. Place and Duration of Study Clinical Biochemistry Research Laboratory, Department of Biochemistry, University of Karachi. The investigation was carried out during 2000 to 2001. Subjects and Male Wistar rats [150-200 g body wt] were selected and divided into control and test groups [n = 5] for comparison. In in-vitro [10 - 1000mM] as well in-vivo [0.5 ' 30 mg/kg body wt.] studies, fluoxetine showed a statistically significant inhibition of rat liver tryptophan pyrrolase [tryptophan-2,3-dioxygenase; EC 1.13.11.11] activity. Significant increases were noted at 10 and 30 mg/kg doses in brain, serum [total and free] and liver L-tryptophan concentrations. Similarly, serum non-estrified free fatty acids showed a significant increase at both doses. There was no effect on serum glucose and albumin concentrations. It is suggested that major mechanism of action of fluoxetine is that of elevating brain tryptophan concentration and hence 5-HT synthesis by increasing the availability of circulating tryptophan to the brain secondarily to inhibition of major tryptophan degrading enzyme, hepatic tryptophan pyrrolase. It is assumed that fluoxetine inhibits the binding of apoenzyme form of tryptophan pyrrolase with its cofactor haem. The results are discussed in relation to possible involvement of disturbed hepatic tryptophan metabolism in depressive illness