Dose response and time course of alterations in tryptophan metabolism by 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 tryptophan and a consequent increase in brain serotonin (5-HT) metabolism may be associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lethality. In the present study we have studied the dose-response and time course relationships of these phenomena in the most TCDD-susceptible Long-Evans (Turku AB [L-E]; LD50 ca. 10 micrograms/kg) and the most TCDD-resistant Han/Wistar (Kuopio [H/W], LD50 > 7200 micrograms/kg) rat strains. Six days after exposure, there was a dose-related increase in brain 5-HT turnover and plasma free tryptophan in both male and female L-E rats. Pair-fed control rats did not exhibit changes in these parameters. The increases 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 rats no such increases in brain 5-HT metabolism or plasma free tryptophan were discernible. Similarly, body weight changes were minor in H/W rats despite almost 1000-fold greater doses of TCDD. Large neutral amino acids other than tryptophan were 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 physiological factors known to be carried by albumin were determined. Nonesterified 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 parameter and plasma free tryptophan. A moderate increase in plasma NEFA was also seen in pair-fed control rats. Bilirubin was dose dependently increased in the plasma of female L-E rats and there was a good correlation between plasma free tryptophan and total (r = 0.779) or conjugated (r = 0.825) bilirubin. The concentration of albumin tended to be suppressed in female L-E rats. The main tryptophan metabolizing enzyme, hepatic 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 body weight was remarkably similar, with both effects emerging early (1 or 2 days) after TCDD exposure and showing progressive development thereafter until the last time point of 10 days.(ABSTRACT TRUNCATED AT 400 WORDS)
Unkila
M
M
National Public Health Institute, Department of Toxicology, Kuopio, Finland.
Pohjanvirta
R
R
MacDonald
E
E
Tuomisto
J T
JT
Tuomisto
J
J
D000597:Amino Acids, Branched-Chain / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D008099:Liver / Q000201:enzymology; D008297:Male; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012709:Serum Albumin / Q000187:drug effects; D012737:Sex Factors; D013997:Time Factors; D014364:Tryptophan / Q000097:blood*; D014366:Tryptophan Oxygenase / Q000378:metabolism
D000597:Amino Acids, Branched-Chain; D005230:Fatty Acids, Nonesterified; D000072317:Polychlorinated Dibenzodioxins; D012709:Serum Albumin; D012701:Serotonin; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D001663:Bilirubin