This application proposes to continue studies of the transport of plasma protein-bound steroid and tyroid hormones into brain and other organs in vivo. The work advances a new concept in endocrinology the protein-bound hormone hypothesis, which holds that the biologically active hormone in blood for many tissues in the body is the protein-bound, either the albumin-bound or the globulin-bound, moiety not the free fraction. The work is divided into three main areas: (a) a physiologic model to test the metabolic diversity underlying the phenomena of transport of protein-bound hormones; (b) a physiologic based steady state mathematical model; the parameter estimates obtained from the physiologic studies will be used in the mathematical model, which employs seven differential equations and a full analytic solution; (c) a biochemical model using isolated brain capillaries to investigate the presence of endothelial plasma protein receptors or inhibitors that possibly mediate the transport process. The physiologic studies will extend the previous work on brain and liver to other organs such as kidney and salivary gland. The salivary gland studies, in particular, are important since preliminary data indicate only the free hormone is available in salivary gland capillaries in vivo. The mathematical modeling studies are novel in that they put forward, for the first time, a physiologic based model of hormone transport in vivo which allows for the prediction of both free and bound concentrations of hormone inside cells. The biochemical mechanism mediating the transport of protein-bound hormones in vivo will be aimed initially at describing receptors for plasma proteins on capillaries. In addition, the hypothesis that the endothelial membrane releases inhibitors of plasma protein hormone binding will be investigated using high concentrations of brain capillaries, e.g., 5 mg protein/ml in a centrifugal isodialysis technique. This allows for rapid measurement of free hormones in small samples (200 MuL) and is suited to establishing an in vitro model of brain that duplicates the physiologic density of brain capillaries (i.e., about 5% of brain water space). An understanding of the biochemistry underlying the transport of protein-bound hormones is considered essential to a complete understanding of this important physiologic process.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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University of California Los Angeles
Schools of Medicine
Los Angeles
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Ellison, S A; Pardridge, W M (1990) Reduction of testosterone availability to 5 alpha-reductase by human sex hormone-binding globulin in the rat ventral prostate gland in vivo. Prostate 17:281-91
Lupo, M A; Cefalu, W T; Pardridge, W M (1990) Kinetics of lactate transport into rat liver in vivo. Metabolism 39:374-7
Crandall, R L; Pardridge, W M (1989) Triiodothyronine bound to red blood cells is not available for transport through the blood-brain barrier. Neurochem Res 14:657-9
Terasaki, T; Nowlin, D M; Pardridge, W M (1988) Differential binding of testosterone and estradiol to isoforms of sex hormone-binding globulin: selective alteration of estradiol binding in cirrhosis. J Clin Endocrinol Metab 67:639-43
Terasaki, T; Pardridge, W M (1988) Differential binding of thyroxine and triiodothyronine to acidic isoforms of thyroid hormone binding globulin in human serum. Biochemistry 27:3624-8
Sakiyama, R; Pardridge, W M; Musto, N A (1988) Influx of testosterone-binding globulin (TeBG) and TeBG-bound sex steroid hormones into rat testis and prostate. J Clin Endocrinol Metab 67:98-103
Pardridge, W M; Eisenberg, J; Fierer, G et al. (1988) Developmental changes in brain and serum binding of testosterone and in brain capillary uptake of testosterone-binding serum proteins in the rabbit. Brain Res 466:245-53
Pardridge, W M (1988) Selective delivery of sex steroid hormones to tissues by albumin and by sex hormone-binding globulin. Oxf Rev Reprod Biol 10:237-92
Pardridge, W M (1988) Selective delivery of sex steroid hormones to tissues in vivo by albumin and by sex hormone-binding globulin. Ann N Y Acad Sci 538:173-92
Terasaki, T; Pardridge, W M (1988) Restricted transport of 3'-azido-3'-deoxythymidine and dideoxynucleosides through the blood-brain barrier. J Infect Dis 158:630-2

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