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Reactivities of Amino Acids and Proteins with Iodine
Published in Erwin Regoeczi, Iodine-Labeled Plasma Proteins, 2019
Radioactive iodotyrosines can be produced by a variety of methods, the simplest probably being iodination of the free amino acid by radioactive triiodide.252 Proportions of the mono- and diiodo derivatives to form can be manipulated by varying the molar ratio of the reactants as well as the polarity of the medium (see Section I.F.2.a). Finally, the two types of iodotyrosine are separated by one of the techniques discussed in Section C. Mostly (≃95%) monoiodotyrosine of high specific activity is obtained by the lactoperoxidase-catalyzed iodination of tyrosine in the absence of added carrier under the conditions described by Hadi and colleagues.91 Tyrosine can also be labeled to high specific activities on a microgram490 or submicrogram170,491 scale by using chloramine-T. Hallaba and colleagues492 used IC1 to label tyrosine in borate buffer pH 8.0. Although the relative yields of the mono- and diiodo derivatives could be shifted considerably either way by carrying out the reaction at different tyrosine/ICl ratios, yet always a mixture of both forms was obtained. Separation was afforded on small columns of Dowex® 1-X8 (see Chapter 4, Section III. A. 1) by eluting monoio- dotyrosine with 0.2 M ammonium acetate, pH 5.8, and diiodotyrosine with glacial acetic acid.
Principles of Radioiodination and Iodine-Labeled Tracers in Biomedical Investigation †
Published in Garimella V. S. Rayudu, Lelio G. Colombetti, Radiotracers for Medical Applications, 2019
Mrinal K. Dewanjee, Shyam A. Rao
To determine the sites of radioiodination in the labeled protein, radioiodinated proteins were hydrolyzed by acidic, alkaline, neutral, or enzymatic methods.457,461 Acid hydrolysis is unacceptable for the present studies because iodotyrosine and iodohisti-dine break down in acid. The pronase enzyme exhibited the broadest substrate specificity and has maximal activity at neutral pH, in which protein iodine bonds are maximally stable. The iodinated amino acids resulting from proteolysis were separated by ion exchange chromatography. The IC1 and enzymatic methods yielded large amounts of iodotyrosine with smaller amounts of other iodinated amino acids. The chloramine-T product spectrum varied with the ratio of chloramine-T to protein, whereas the product spectrum457 by the electrolytic method was a complex function of reaction conditions. The different methods of iodination thus lead to some differences in the site of iodination which correlate with stability of the protein iodine bond.
Thyroid disease and pregnancy
Published in David S. Cooper, Jennifer A. Sipos, Medical Management of Thyroid Disease, 2018
Alisha N. Wade, Susan J. Mandel
Antithyroid Drugs. Antithyroid drugs are the main treatment for Graves’ disease during pregnancy. Propylthiouracil (PTU) and methimazole (or carbimazole, available in countries outside the United States) (MMI, Tapazole [Pfizer]/or CMZ) have both been used during gestation. They inhibit thyroid hormone synthesis via a reduction in iodine organification and iodotyrosine coupling (see Chapter 2, “The Diagnostic Evaluation and Management of Hyperthyroidism...”). Pregnancy itself does not appear to alter the maternal pharmacokinetics of MMI, although serum PTU levels may be lower in the latter part of gestation compared to the first and second trimesters (85). PTU is more extensively bound to albumin at physiologic pH, whereas MMI is less bound, which hypothetically might result in increased transplacental passage of MMI relative to PTU. Historically, PTU was preferred over MMI, partly due to early experimental data suggesting that PTU, which is more highly protein bound than MMI, had more limited transplacental passage than MMI (86). Since then, however, other studies have found that both drugs readily cross the placenta (87, 88). No such data evaluating simultaneous maternal and cord levels are available for MMI.
Effect of molecular size on interstitial pharmacokinetics and tissue catabolism of antibodies
Published in mAbs, 2022
Hanine Rafidi, Sharmila Rajan, Konnie Urban, Whitney Shatz-Binder, Keliana Hui, Gregory Z. Ferl, Amrita V. Kamath, C. Andrew Boswell
Each molecule was labeled in separate reactions with two radionuclides, iodine-125 (125I) and indium-111 (111In), and the purified tracers were later combined for IV administration. The dual-tracer approach differentiates between intact and internalized/degraded molecules.19,59 When iodinated antibodies are internalized and degraded, the free-radioactive iodide and/or iodotyrosine rapidly diffuses from the cell and is cleared from the systemic circulation.24 Consequently, the 125I signal represents primarily intact antibody. In contrast, the same internalization and lysosomal degradation of 111In-labeled antibodies yields an 111In-DOTA-amino acid adduct that is cell impermeable and accumulates over time. Therefore, subtracting 125I signal from 111In signal can be used to approximate the total internalized/degraded (catabolized) antibody.70
Novel Methods to Improve the Efficiency of Radioimmunotherapy for Non-Hodgkin Lymphoma
Published in International Reviews of Immunology, 2019
Mahsa Eskian, MirHojjat Khorasanizadeh, Pier Luigi Zinzani, Tim M. Illidge, Nima Rezaei
As was mentioned earlier, conventional iodine radiolabels are rapidly released from the cells as iodotyrosine after Ab degradation in lysosomes. This problem is partially responsible for poor localization of radiation to the tumoral cells. Besides using chelating agents, another way to overcome this problem, and therefore to enhance tumor to normal organs radiation ratio is the use of “residualizing” radiolabels.
The S-oxidation of S-carboxymethyl-L-cysteine in hepatic cytosolic fractions from BTBR and phenylketonuria enu1 and enu2 mice
Published in Xenobiotica, 2019
Glyn B. Steventon, Stephen C. Mitchell
The identity of the enzyme responsible for the C-oxidation of L-Phe and S-oxidation of SCMC in wt/wt (BTBR) female hepatic cytosolic fractions was investigated using selective antibody and chemical inhibitors (Table 3 and Figure 4 ). The effect of the large aromatic hydroxylase (PAH, tyrosine hydroxylase and tryptophan hydroxylase) antibody, PH8, can be seen to significantly inhibit both L-Phe (97–98%) and SCMC (93–99%) metabolism at both concentrations used. The specific PAH (4-chlorophenylalanine), tyrosine hydroxylase (3-iodotyrosine) and tryptophan hydroxylase (6-fluorotryptophan) inhibitors were investigated to see what effect these chemical inhibitors had on the oxidation of both L-Phe and SCMC. There was no effect of 3-iodotyrosine and 6-fluorotryptophan on the metabolism of the two substrates but 4-chlorophenylalanine significantly inhibited the C-oxidation of L-Phe and the S-oxidation of SCMC at all concentrations used (22–99% for L-Phe and 67–101% for SCMC, Table 3). The effectiveness of SCMC as an inhibitor of the C-oxidation of L-Phe and the effectiveness of L-Phe as an inhibitor of the S-oxidation of SCMC was also investigated. SCMC only caused significant inhibition of L-Phe metabolism at the highest concentration used (5.0 mM causing 27.0% inhibition, p < 0.05 Tukey’s test). L-Phe, however, caused significant inhibtion of the S-oxidation of SCMC at all concentrations used (18–94% inhibition, Table 3). The effects of the Fe2+ chelator, 2’2-dipyridyl and a broad spectrum of NOS inhibitors was also investigated. The NOS inhibitors were found to have no inhibitory effect on the metabolism of L-Phe and SCMC (Table 3) but 2’2-dipyridyl was found to have significant inhibition of both the C-oxidation of L-Phe and the S-oxidation of SCMC at all concentrations used (Table 3). The correlation of the production of L-Tyr and SCMC (R/S) S-oxides production in 20 female wild type hepatic cytosolic fractions was also examined and was found to be highly linearly correlated with a r2 value of 0.88 (Spearman's Rank correlation coefficient, p < 0.01) and a r value of 0.94 (Figure 3).