1. The effects of the administration of oestradiol and vitamin B6 on tryptophan metabolism in the rat have been assessed by measurement of the release of 14CO2 from [14C]tryptophan, in vivo, in order to determine whether, and to what extent, the abnormalities of tryptophan metabolism that are associated with oestrogen administration can be attributed to drug-induced vitamin B6 deficiency or depletion. Two positional isomers of [14C]tryptophan have been used; [ring-2-14C]tryptophan as an index of the activity of tryptophan oxygenase (L-tryptophan: oxygen oxidoreductase (decyclizing), EC 1.13.11.11) and [methylene-14C]trytophan as an index of the activity of kynureninase (L-kynurenine hydrolase, EC 3.7.1.3).2. The administration of 500 μg oestradiol/kg body-weight led to a reduction in the release of 14CO2 from both positional isomers of tryptophan, suggesting that the activities of both tryptophan oxygenase and kynureninase are reduced following oestrogen treatment. The kinetics of the release of 14CO2 from [methylene-14C]tryptophan after the administration of oestradiol were compatible with competitive inhibition of kynureninase by oestradiol or a metabolite.3. The administration of 10 mg pyridoxine hydrochloride/kg body-weight also reduced the production of 14CO2 from both positional isomers of 14C]tryptophan, suggesting some toxicity of such a high dose of the vitamin.4. In animals which had received the supplementary dose of vitamin B6, the administration of oestradiol led to further reduction in the production of 14CO2 from [ring-2-14C]tryptophan, suggesting a further reduction in the activity of tryptophan oxygenase, and an increase in the production of 14CO2 from [methylen-14C]tryptophan, but with a delay in the peak of production.5. These results confirm that there is no induction of tryptophan oxygenase by oestradiol, but rather reduced activity of the enzyme after the administration of a relatively high dose of the hormone. They also confirm that the inhibition of kynureninase by oestrogen metabolites that has been reported previously in partially-purified enzyme preparations also occurs in vivo.6. It is suggested that the abnormal results of the tryptophan load test that have been reported in women receiving oestrogens, and which have been interpreted as indicating some extent of drug-induced vitamin B6 deficiency, can be accounted for by the inhibition of tryptophan metabolism by oestrogens or their metabolites. Therefore it seems likely that the practice of administering supplements of vitamin B6 to women receiving oestrogens may not be appropriate, and indeed may exacerbate the changes in tryptophan metabolism that result from the administration of oestrogens. The tryptophan load test would appear to be unreliable as an index of vitamin B6 nutritional status in women receiving oestrogens.
Effect of acetoacetate administration on urinary and tissue vitamin B6 in rats
