Oral l-thyroxine (T4) therapy is used to treat human hypothyroidism but T4 fed to teleost fish does not raise plasma thyroid hormone (TH) levels nor induce growth, even though oral 3,5,3'-triiodo-l-thyronine (T3) is effective. This suggests a major difference in TH metabolism between teleosts and humans, often used as a starting thyroid model for lower vertebrates. To gain further insight on the proximate (mechanistic) and ultimate (survival value) factors underlying this difference, the several steps in TH homeostasis from intestinal TH uptake to hypothalamic-hypophyseal regulation were compared between humans and teleosts, and following dietary TH challenges. A major proximate factor limiting trout T4 uptake is a potent constitutive thiol-inhibited intestinal complete T4 deiodination that is ineffective for T3. At the hepatic level, T4 deiodination, conjugation and extensive biliary excretion with negligible T4 enterohepatic recycling can further block teleost T4 uptake to plasma. Such protection of plasma T4 from dietary T4 may be particularly critical for piscivorous fish consuming thyroid tissue, rich in T4 but not T3. It would prevent disruption by unregulated ingested T4 of the characteristic acute and transient changes in teleost plasma T4 due to diel rhythms, food intake and stress-related factors. These marked natural short-term fluctuations in teleost plasma T4 levels are enabled by the relatively small and rapidly-cleared plasma T4 pool, stemming largely from properties of the plasma T4-binding proteins. Humans, however, due mainly to plasma T4-binding globulin, have a relatively massive circulating pool of T4 and an extremely well-buffered free T4 level, consistent with the major TH role in regulating basal metabolic rate. Furthermore, this large well-buffered and slowly-cleared plasma T4 pool, in conjuction with enterohepatic recycling and relaxation of hypothalamic-hypophyseal negative feedback, allows humans to temporarily 'store' ingested T4 in plasma, thereby sparing endogenous TH secretion and conserving thyroidal iodine reserves. Indeed, iodine conservation is likely the key ultimate factor determining the divergent evolution of the human and teleost systems. For humans, ingested iodine in the form of I-, or TH and their derivatives, is the sole iodine source and may be limiting in many environments. However, most freshwater teleosts, in addition to their ability to assimilate dietary I-, can derive sufficient I- from their copious gill irrigation, with no selective advantage in absorbing dietary T4 which would disrupt their natural acute and transient changes in plasma T4. Thus T4 may act also as a vitamin (vitamone) in humans but not in teleosts; in contrast, T3, naturally ingested at much lower levels, may act as a vitamone in both humans and teleosts.
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