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TPO is the key enzyme involved in the thyroid hormone synthesis. The human TPO (hTPO) gene locates on chromosome 2 and consists of 17 exons and 16 introns. Compared with other peroxidases, hTPO is 42% homologous with granulocyte myeloperoxidase. Thyroid cells contain multiple TPO mRNA transcripts of various size. However, the reason is unknown. TTF-1 and TTF-2 are known to regulate TPO gene expression. Moreover, the other factors are becoming clear to regulate it. Congenital TPO defects result in hypothyroidism and goiter. Recent studies clarify a human mutation causing TPO deficiency.

Most thyroxine (T4) secreted from the thyroid is deiodinated in peripheral tissues. At least three isozymes are known in iodothyronine deiodinase which catalyzes the conversion of T4 to triiodothyronine (T3) or reverse T3. Type I 5'-deiodinase (5'D-I) exists in most tissues including the liver, kidney and thyroid. Type II 5'-deiodinase (5'D-II) which exists mainly in the brain, pituitary, brown fat and placenta plays an important role in the saturation of intracellular T3 receptor. Type III enzyme (D-III) which deiodinases the five positions of T3 is considered to modulate the T3 content by regulating its degradation. The complementary DNA (cDNA) for the rat and human 5'D-I has recently been cloned. 5'D-I contains a rare amino acid selenocysteine, which is essential for normal deiodinative function in humans as well as rats. On the other hand, 5'D-II, whose molecular weight is much heavier than that of 5'D-I, does not contain selenocysteine and its cDNA has not been sequenced. Little is known about the molecular characteristics of D-III. Further studies are needed to clarify the molecular mechanism by which deiodinase proteins are produced in various circumstances and to investigate the meticulous aspects of metabolic pathways other than deiodination.

BioBreeding/Worcester (BB/W) rats develop insulin dependent diabetes mellitus (IDDM) and lymphocytic thyroiditis (LT) spontaneously. Our previous studies have shown that BB/W (Saitama-Tokyo colony) rats develop LT at about 10 weeks of age. Their serum TSH values increase as LT extends, although their serum thyroid hormone levels remain normal. This indicates that BB/W rats suffer from subclinical hypothyroidism. To investigate whether BB/W rats have a defect in iodide metabolism, the thyroidal radioactive iodine uptake (RAIU) in BB/W rats was examined. Thyroidal RAIU at 3hr in both 8 and 16 week-old BB/W rats was significantly higher than that in age-matched normal Wistar rats. On the other hand, BB/W rats had significantly lower 48hr thyroidal RAIU than normal Wistar rats. This suggests that BB/W rats appear to have some defects in iodide metabolism, especially in iodide organification even before the development of LT. The expression of thyroid peroxidase (TPO) and thyroglobulin (Tg) mRNA in BB/W and Wistar rats was then examined using the Northern blot analysis. The expression of both TPO and Tg mRNA was greatly decreased in BB/W rats compared with that in Wistar rats despite the high serum TSH levels in BB/W rats. This indicates that BB/W rats may have pretranslational defects in TPO and Tg synthesis, resulting in the impaired thyroid hormone synthesis. In the present study, it has been demonstrated that BB/W rats appear to have a defect(s) in iodide metabolism possibly due to some abnormalities in TPO and Tg synthesis.

Thyroid Peroxidase (TPO) is a key enzyme in the synthesis of thyroid hormone and is a major thyroid microsomal antigen corresponding to anti-microsomal autoantibodies in thyroid autoimmune diseases. We studied the autoantigenicity, thyroiditogenicity and gene structure of TPO. In micro-ELISA using human TPO as a target, all sera from patients with anti-microsomal antibodies contained IgG class of antibodies to TPO and some sera had IgM class of antibodies. The competitive inhibition test revealed that TPO is the major thyroid microsomal antigen. Experimental murine thyroiditis was successfully induced by the immunization of porcine TPO. Susceptibility of thyroiditis in each strain was very different from that of thyroiditis induced by thyroglobulin. T-cell line specific for porcine TPO could mediate thyroid lesions. Two kinds of full length cDNAs to human TPO were isolated from cDNA library which was constructed from mRNA purified from thyroid with Graves' disease. The longer one consisted of 3,048 nucleotides and its open-reading-frame was likely to encode 933 amino acids. The shorter one lacked 171 nucleotides at the middle portion of the longer one. The structure-gene for human TPO was located on 2q and consisted of 17 exons. One hundred and seventy-one nucleotides deleted in the shorter cDNA exactly corresponded to the 10th exon.

Human thyroid peroxidase (TPO) was found to bind with both IgG and IgM from patients with autoimmune thyroid diseases. Furthermore, binding of IgG to microsomes was inhibited by TPO. Patients' IgG that passed through an antigen column packed with TPO-coupled Sepharose 4 B beads lost their hemagglutinating activity in microsome hemagglutination test. Various strains of mice were immunized with porcine TPO emulsified in complete Freund's adjuvant. Both C 57 BL/6 and C 57 BL/10 mice showed mononuclear cell infiltration in the thyroid with very high incidences of thyroiditis. The strains of mice showing thyroiditis were very different from high responder strains that were immunized with murine thyroglobulin. Cloning of human TPO cDNA was attempted to deduce the primary structure of human TPO. Using three kinds of oligonucleotides as probes, two cDNAs, 2.8 and 2.4 kb, were selected from a cDNA library constructed from mRNA purified from Graves' disease thyroid. Sequencing of cDNAs revealed that shorter cDNA lacked 171 nucleotides at the middle portion of the longer cDNA. Primer extension analysis of mRNA indicated that the full length cDNA of human TPO consists of 3,048 nucleotides and its open reading frame codes 933 amino acids.