DOSE-RESPONSE AND TIME-COURSE OF ALTERATIONS IN TRYPTOPHAN-METABOLISMBY 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (TCDD) IN THE MOST TCDD-SUSCEPTIBLE AND THE MOST TCDD-RESISTANT RAT STRAIN - RELATIONSHIP WITH TCDD LETHALITY

It has previously been shown that an increase in plasma free tryptopha n and a consequent increase in brain serotonin (5-HT) metabolism may b e associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lethality . In the present study we have studied the dose-response and time cour se relationships of these phenomena in the most TCDD-susceptible Long- Evans (Turku AB [L-E]; LD50 ca. 10 mu g/kg) and the most TCDD-resistan t Han/Wistar (Kuopio [H/W], LD50 > 7200 mu g/kg) rat strains. Sis days after exposure, there was a dose-related increase in brain 5-HT turno ver and plasma free tryptophan in both male and female L-E rats. Pair- fed control rats did not exhibit changes in these parameters. The incr eases emerged in the dose range known to elicit lethality in L-E rats. Furthermore, the increases in plasma free tryptophan correlated well with the changes in body weight caused by TCDD. In contrast, in H/W ra ts no such increases in brain 5-HT metabolism or plasma free tryptopha n were discernible. Similarly, body weight changes were minor in H/W r ats despite almost 1000-fold greater doses of TCDD. Large neutral amin o acids other than tryptophan w ere not markedly changed in the plasma of either rat strain. In attempts to identify the mechanism by which TCDD might affect tryptophan binding to albumin, some other physiologi cal factors known to be carried by albumin were determined. Nonesterif ied fatty acids (NEFA) in the plasma were dose dependently elevated in male and female L-E rats and there was a moderate or good correlation (r = 0.654 for male and r = 0.731 for female rats) between this param eter and plasma free tryptophan. A moderate increase in plasma NEFA wa s also seen in pair-fed control rats. Bilirubin was dose dependently i ncreased in the plasma of female L-E rats and there was a good correla tion between plasma free tryptophan and total (r = 0.779) or conjugate d (r = 0.825) bilirubin. The concentration of albumin tended to be sup pressed in female L-E rats. The main tryptophan metabolizing enzyme, h epatic tryptophan pyrrolase, was inhibited in female L-E rats but not in male L-E rats or H/W rats of either gender. Moreover, in female L-E rats the time course for changes in plasma free tryptophan and in bod y weight was remarkably similar, with both effects emerging early (1 o r 2 days) after TCDD exposure and showing progressive development ther eafter until the last time point of 10 days. Although the changes in p lasma free tryptophan do not have to be causally related with TCDD ano rexia, the present results show convincingly that the two phenomena ar e tightly associated. Resolving the mechanism by which TCDD changes tr yptophan binding to albumin may give insight into the as yet unknown p rimary alterations in the acute toxicity of TCDD. (C) 1994 Academic Pr ess, Inc.