Increased plasma clearance rate of thyroxine despite decreased 5'-monodeiodination: study with a peroxisome proliferator in the rat.
In euthyroid rats a 17-day treatment with nafenopin, a hypolipidemic agent and peroxisome proliferator, decreased serum total and free T4 concentrations to 32 +/- 5% and 62 +/- 8% (mean +/- SEM; n = 10), respectively, with no change in serum T3 and TSH concentrations. In methimazole-treated rats infused with 3 nmol T4/day/100 g BW, the nafenopin inhibitory effect was not significantly different from that in euthyroid rats. Nafenopin treatment had the following effects on peripheral T4 and T3 metabolism in euthyroid rats. The plasma clearance rate of T4 (PCR), which was measured by Alzet minipump infusion of tracer, was increased 2-fold (1.58 +/- 0.09 vs. 0.82 +/- 0.06 ml/h.100 g BW; P less than 0.001; n = 5), while the PCR of T3 was decreased (37.5 +/- 1.3 vs. 53.8 +/- 1.8; P less than 0.001; n = 5). The fecal clearance rate of radioactivity derived from T4 was increased 2-fold (1.93 +/- 0.10 vs. 0.77 +/- 0.07 ml/h.100 g BW), whereas the urinary clearance rate was not significantly modified. The 5'-deiodinase (5'D) activity, measured by deiodination of labeled rT3, was strongly inhibited in liver and kidney, not modified in brown fat and anterior pituitary, and increased in cerebral cortex. In methimazole-treated rats substituted with isopropyl-diiodothyronine only hepatic 5'D activity was decreased. It is concluded that the decrease in serum total and free T4, without alteration in serum T3 and TSH concentrations, resulting from nafenopin treatment is mainly due to changes in peripheral T4 and T3 metabolism, since it is also observed in T4-substituted animals. The increased PCR of T4 cannot be explained by an increase in deiodination activity, since the major 5'D pathways are inhibited after nafenopin treatment, and the urinary clearance rate is not modified. It can partly be explained by an increase in the fecal clearance rate of T4, which could be due to an increase in glucoronoconjugation. In addition, nafenopin was found to be a weak competitor of T4 binding to serum proteins, leading to a small increase in the free T4 fraction which might also contribute to the increased T4 PCR. The decrease in T3 PCR remains to be explained.
Kaiser
C A
CA
Department of Medicine, University of Geneva, Switzerland.
Seydoux
J
J
Giacobino
J P
JP
Girardier
L
L
Burger
A G
AG
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D004104:Diiodothyronines / Q000494:pharmacology; D005243:Feces / Q000032:analysis; D006728:Hormones; D007037:Hypothyroidism / Q000139:chemically induced / Q000201:enzymology; D007453:Iodide Peroxidase / Q000378:metabolism*; D007457:Iodine Radioisotopes; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008713:Methimazole; D008830:Microbodies / Q000187:drug effects*; D009255:Nafenopin / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood* / Q000378:metabolism / Q000652:urine; D014284:Triiodothyronine / Q000097:blood
D004104:Diiodothyronines; D006728:Hormones; D007457:Iodine Radioisotopes; D011422:Propionates; D014284:Triiodothyronine; D009255:Nafenopin; C027594:isopropyl-diiodothyronine; D008713:Methimazole; D013972:Thyrotropin; D007453:Iodide Peroxidase; D013974:Thyroxine