Ron Wang

Abstract

Multiple alterations of serum thyroid hormone metabolism have been noted in essentially all severe systemic nonthyroidal illnesses (Nil). This spectrum of abnormalities is collectively termed the “euthyroid sick syndrome”. One putative mechanism is the presence of circulating thyroid hormone binding inhibitors. Salsalate and salicylate are known to be such inhibitors. The objectives of this study are: to investigate the thyroid hormone changes induced in healthy people by salsalate, and to investigate the mechanisms of salsalate action, as a model for the euthyroid sick syndrome. This dissertation includes: (1) Study of the effect of salsalate on serum thyroid hormone levels in healthy people. (2) Study of 14C-salsalate and 14C-salicylate binding to serum thyroid hormone binding proteins. (3) Development of an “inhibitor assay” to detect the circulating thyroid hormone binding inhibitors. (4) Study of the inhibitory effects of salsalate, salicylate and furosemide using the inhibitor assay.

The thyroid hormone changes following a single oral dose of salsalate exhibited the major characteristics of the euthyroid sick syndrome, which are the inhibition of T4binding to serum proteins, the inhibition of peripheral 5'- monodeiodination of T4 and the derangement of TSH regulation. Salsalate’s action was more complicated than that of simple inhibition of T4 binding to serum proteins. Compartmental shifts in thyroid hormones may play a role in producing these thyroid hormone changes and possibly the thyroid hormone abnormalities in NTI. Our studies indicated that salsalate and salicylate inhibited T4 binding to thyroid hormone binding globulin (TBG) and the inhibitory potency of salsalate was approximately 100 fold greater than that of salicylate. Salsalate and salicylate inhibited T4 binding to transthyretin and albumin to a much smaller degree than to TBG. Even though more than 90% of salsalate in serum was bound to serum proteins, only small fractions of both salsalate and salicylate were bound to TBG.

To our knowledge, this is the first report of the thyroid hormone changes following a single oral dose of salsalate and the first report of a systematic study of the mechanisms of salsalate effects on inhibition of T4 binding to serum binding proteins.

LLU Discipline

Biochemistry

Department

Biochemistry

School

Graduate School

First Advisor

R. Bruce Wilcox

Second Advisor

E. Clifford Herrmann

Third Advisor

John Leonora

Fourth Advisor

Jerald C. Nelson

Fifth Advisor

Charles W. Slattery

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

1997

Date (Title Page)

3-1997

Language

English

Library of Congress/MESH Subject Headings

Euthyroid Sick Syndrome -- etiology; Thyroid Hormones -- metabolism; Receptors, Thyroid Hormone; Thyroxine-Binding Proteins

Type

Dissertation

Page Count

xiv; 174

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

Download

Included in

Biochemistry Commons

Share

COinS