The goal of this work is the development of a firm mathematical and experimental foundation that will lead to further understanding of how the lipophilic hormones (thyroxine, triiodothyronine, cortisol, the sex steroids, and vitamin D) distribute between plasma and tissues in vivo. To this end, the proposed research will focus on the following specific objectives: 1) The development of a general mathematical model that will allow prediction of tissue hormone concentrations, for any given hormone and under any given set of conditions, from knowledge of the relevant rate constants and from measurements made in bulk plasma. This undertaking will include a complete mathematical delineation of the conditions under which the free hormone hypothesis is and is not expected to be valid. Computer-assisted technology will be used for this purpose. 2) A determination of the mechanism(s) (i.e., via the free pool or via protein-bound pools) of tissue uptake in vivo for thyroxine, triiodothyronine, cortisol, the sex steroids, and vitamin D. This will require for each hormone measurement of the unbound (free) concentration in plasma (equilibrium dialysis of centrifugal ultrafiltration-dialysis will be used), the rate constants for dissociation from plasma binding proteins (a rapid filtration assay will be used), and the rate constant for tissue uptake of free hormone (an in vitro rat liver perfusion system will be used). These findings will be interpreted in terms of the general mathematical model developed. In addition, whenever there is reason to postulate active transport of free hormone, an attempt will be made to determine the location of that transport (i.e., at the plasma membrane or the nuclear membrane). 3) Documentation of whether changes in factors other than plasma hormone concentrations ever affect intracellular hormone concentrations in vivo. Such factors might include the influx and efflux rate constants or, under certain conditions, the elimination rate constant. As a first step, hepatic uptake of thyroxine in fed vs. fasted rats will be considered. 4) A determination of the generalizability of the concepts of in vivo hormone transport developed here. The nonhormone lipids cholesterol and vitamin E will be considered in these terms. Off rate constants, tissue uptake rate constants, and unbound concentrations in plasma will be measured in anticipation that new insights into the transport and metabolism of these lipids will be obtained.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK040355-03
Application #
3463497
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
3
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Jaume, J C; Mendel, C M; Frost, P H et al. (1996) Extremely low doses of heparin release lipase activity into the plasma and can thereby cause artifactual elevations in the serum-free thyroxine concentration as measured by equilibrium dialysis. Thyroid 6:79-83
Mendel, C M (1994) A novel assay for comparing affinity constants of ligands with small differences in affinity: application to low-density lipoproteins. Anal Biochem 216:328-34
Mendel, C M (1992) Preliminary evaluation of a fluorescence polarization immunoassay (Abbott TDx) for estimating serum free thyroxine concentrations in patients with critical nonthyroid illness and low total thyroxine concentrations in serum. Clin Chem 38:1916-7
Mendel, C M (1992) The free hormone hypothesis. Distinction from the free hormone transport hypothesis. J Androl 13:107-16
Mendel, C M; Cavalieri, R R; Kohrle, J (1992) Thyroxine (T4) transport and distribution in rats treated with EMD 21388, a synthetic flavonoid that displaces T4 from transthyretin. Endocrinology 130:1525-32
Murai, J T; Mendel, C M; Siiteri, P K (1991) Free fatty acids do not influence the concentrations of free steroid hormones in serum under physiological conditions. J Clin Endocrinol Metab 72:137-9
Mendel, C M; Laughton, C W; McMahon, F A et al. (1991) Inability to detect an inhibitor of thyroxine-serum protein binding in sera from patients with nonthyroid illness. Metabolism 40:491-502
Mendel, C M; Kuhn, R W; Weisiger, R A (1991) Uptake of corticosterone by the perfused rat liver. Endocrinology 129:27-32
Mendel, C M; Weisiger, R A (1990) Thyroxine uptake by perfused rat liver. No evidence for facilitation by five different thyroxine-binding proteins. J Clin Invest 86:1840-7
Mendel, C M (1990) Rates of dissociation of sex steroid hormones from human sex hormone-binding globulin: a reassessment. J Steroid Biochem Mol Biol 37:251-5

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