Familial dysalbuminaemic hyperthyroxinaemia: studies of albumin binding and implications for hormone action.
The abnormal intermediate-affinity T4 binding to albumin which is characteristic of familial dysalbuminaemic hyperthyroxinaemia (FDH) is dependent on buffer, temperature, and ionic composition. Scatchard analysis of T4-binding to isolated albumin preparations from FDH subjects showed that half the circulating albumin showed the higher-affinity T4 binding site, assuming one site per molecule. Using dextran-charcoal separation at 4 degrees C the T4 affinity (Kd) of purified albumin from FDH subjects was 7.5 nmol/l in phosphate and 17 nmol/l in Tris-Cl- buffer. T4 binding to FDH albumin was inhibited by a range of substances in the order: 8-anilino-1-naphthalene sulphonic acid greater than merthiolate greater than propylthiouracil greater than methyl-thiouracil greater than carbimazole greater than salicylate greater than barbitone. Binding of T4 was competitively inhibited by low concentrations of dithiothreitol (DTT). The effect of DTT 0.1-0.5 nmol/l was reversed by removal of DTT by dialysis. Competition with a range of iodothyronines indicated that the 3', 5'-iodine atoms are most important for binding to this site. Serum binding of salicylate, frusemide, fenclofenac and barbituric acid, and a range of steroid hormones was similar in FDH and normal sera. Serum levels of sex hormone binding globulin (SHBG), were not significantly different from sex-matched controls. Nuclear [125I]-T3 binding sites in circulating lymphocytes from two FDH subjects showed affinities (Kd) of 59 and 79 pmol/l (normal 67 +/- 7 pmol/l, n = 6). These findings suggest that the highly specific binding anomaly of FDH is due to a disulphide-dependent structural change in albumin.(ABSTRACT TRUNCATED AT 250 WORDS)
Barlow
J W
JW
Csicsmann
J M
JM
Meinhold
H
H
Lim
C F
CF
Stockigt
J R
JR
D001796:Blood Protein Disorders / Q000097:blood / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D011485:Protein Binding / Q000187:drug effects; D012709:Serum Albumin / Q000378:metabolism*; D012738:Sex Hormone-Binding Globulin / Q000032:analysis; D013974:Thyroxine / Q000097:blood* / Q000378:metabolism
D012709:Serum Albumin; D012738:Sex Hormone-Binding Globulin; D013974:Thyroxine; D004229:Dithiothreitol