Comparison of the toxicity of orally administered L-triiodothyronine (T3) in rat and cynomolgus monkey.
Oral administration of L-triiodothyronine (L-T3) (0.015-1 mg/kg) for 30 days to mature rats or cynomolgus monkeys resulted in both species in a high mortality at 1 mg/kg (after 2 weeks of treatment) and a progressive loss in body weight. Dose-related elevations in plasma marker enzymes occurred, mainly after 1-2 weeks of treatment. The approximate no-effect dose for these changes was around 0.015-0.020 mg/kg for both rat and primate. The large elevations of leucine aminopeptidase (LAP) at 1 mg/kg L-T3 in monkey indicated hepatocellular toxicity although in the rat such large increases in alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were not seen. L-T3 also showed little toxicity to rat hepatocytes in vitro. High concentrations of L-T3 (7 x 10(-9) to 7 x 10(-7) M) had minimal effects on parameters of cell viability such as lactate dehydrogenase (LDH) leakage, chromium-51 release and [3H]leucine incorporation. Urinary enzymes in the rat showed a similar profile to those in plasma. Large rises in alkaline phosphatase (AKP) and N-acetyl glucosaminidase (NAG) at 1 mg/kg indicated possible proximal tubular damage although this was not supported histologically. Clinically, in both species L-T3 appeared more toxic to males than females but this was not supported histologically. The histological lesions observed were different in the 2 species. In the monkeys there was extensive lipid vacuolation of hepatocytes and changes in thyroid and adrenal cortex. In the rat there was fine, non-lipid vacuolation of hepatocytes and thyroid changes. In the rat, 2 previously unreported lesions were also noted. There were multinucleated cells in the renal distal tubular epithelium, and focal fibroplasia of serosal surfaces of abdominal viscera.
Atterwill
C K
CK
Department of Toxicology, Smith Kline and French Research Ltd, Herts, U.K.
Kennedy
S
S
Jones
C A
CA
Lee
D M
DM
Davies
S
S
Poole
A
A
D000118:Acetylglucosaminidase / Q000652:urine; D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005969:Glutamate Dehydrogenase / Q000097:blood; D007931:Leucyl Aminopeptidase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D014284:Triiodothyronine / Q000008:administration & dosage / Q000633:toxicity*
D014284:Triiodothyronine; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D000118:Acetylglucosaminidase; D007931:Leucyl Aminopeptidase