Ptu

figure 56-2 Major pathways of thyroid hormone biosynthesis and release.

abbreviations: Tg, thyroglobulin; DIT, diiodotyrosine; MIT, monoiodotyrosine; TPO, thyroid peroxidase; HOI, hypoiodous acid; EOI, enzyme-linked species; PTU, propylthiouracil; MMI, methimazole; ECF, extracellular fluid.

3-Ti 3'-Ti figure 56-3 Pathways of iodothyronine deiodination.

i oR

Two distinct 5'-deiodinase enzymes convert T4 to T3; they are selenoproteins that are encoded by distinct genes and are differentially expressed and regulated. The type I 5'-deiodinase (D1)— which is expressed in the liver, kidney, and thyroid—generates circulating T3 that is used by most peripheral target tissues. D1 is inhibited by a number of drugs, including the antithyroid drug propylthiouracil (see below), propranolol, amiodarone, and glucocorticoids. The decreased plasma T3 levels observed in a variety of nonthyroidal illnesses result from inhibition of D1 and decreased entrance of T4 into cells. D1 is upregulated in hyperthyroidism and downregulated in hypothy-roidism. Type II 5'-deiodinase (D2) is expressed in the brain, pituitary, and skeletal and cardiac muscle and supplies intracellular T3 to these tissues. D2 has a much lower Km for T4 than does D1 (nM vs. uM values) and its activity is unaffected by propylthiouracil. D2 is dynamically regulated by its substrate T4, such that elevated levels of the enzyme are found in hypothyroidism and suppressed levels are found in hyperthyroidism. Thus, D2 appears to autoregulate the intracellular supply of T3 in the brain and pituitary. Inner ring- or 5-deiodination, a major inactivating pathway for T4 and T3, is catalyzed by the type III deiodinase (D3), another selenoprotein that is found in placenta, skin, uterus, and brain.

TRANSPORT OF THYROID HORMONES IN THE BLOOD Iodine circulates as both organic iodine (95%) and inorganic iodide (5%). Most organic iodine is in T4 (90-95%), while T3 contains approximately 5%. Both T4 and T3 are transported in the blood in strong but noncovalent association with plasma proteins.

Thyroxine-binding globulin (TBG) is the major carrier of thyroid hormones. An acidic glycoprotein with a molecular weight of ~63,000, TBG binds one molecule of T4 with very high affinity (Ka ~ 1010 M-1). T3 is bound less avidly. T4, but not T3, also is bound by transthyretin (thyroxine-binding prealbumin), a retinol-binding protein. This protein is present in higher concentration than TBG but has a lower affinity (Ka ~ 107 M-1). Albumin can also bind T4 when the more avid carriers are saturated, but the physiological significance of this binding generally is unclear.

Binding of thyroid hormones to plasma proteins protects the hormones from metabolism and excretion and prolongs their half-lives in circulation. The free (unbound) hormone is a small percentage (about 0.03% of T4 and 0.3% of T3) of the total hormone in plasma. The differential binding affinities for plasma proteins also are reflected in the 10-100-fold differences in circulating hormone concentrations and half-lives of T4 and T3.

Because of the high degree of binding of thyroid hormones to TBG, changes in TBG concentration can have major effects on total serum hormone levels. Certain drugs and a variety of pathological and physiological conditions (e.g., changes in estrogen levels during pregnancy or with administration of oral estrogens) can alter both the amount of TBG and its binding of thyroid hormones (Table 56-1). The increase in TBG induced by estrogen is due to an increase in its sialic acid content that decreases TBG clearance. Since the pituitary responds to and regulates circulating free

Table 56-1

Factors That Alter Binding of Thyroxine to Thyroxine-Binding Globulin

Increase Binding

Decrease Binding

Drugs Estrogens Methadone Clofibrate 5-Fluorouracil Heroin Tamoxifen Selective estrogen receptor modulators

Systemic Factors Liver disease Porphyria HIV infection Inheritance

Glucocorticoids Androgens l-Asparaginase Salicylates Mefenamic Acid Antiseizure medications

(phenytoin, carbamazepine) Furosemide

Inheritance

Acute and chronic illness

CHAPTER 56 Thyroid and Antithyroid Drugs 983

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