thyronines and Liver-Neoplasms

T3 cellular uptake is inhibited in the presence of benzodiazepines (BZs). The structure-activity relationship of BZ inhibition correlates strongly with halogen substitution of the nonfused phenyl ring and indicates that this ring is required for activity. A structure-activity series of thyromimetic (TH) inhibitors of the HepG2 iodothyronine transporter further point out the critical importance of the amino group of the alanine side chain, its L-stereo configuration, and the size of the substituents of the inner and outer phenyl rings. A third series of compounds, reported to interact at related sites, were inactive as HepG2 iodothyronine transport inhibitors, and therefore the potent inhibitors were restricted to the BZ and TH compounds. Using both of these BZ and TH structure-activity series along with computer-assisted molecular modeling techniques, we determined which chemical structural components were important at the transporter interaction site. By superimposing structures from active chemicals, excluding residues from poor inhibitors, and incorporating molecular electropotential data, we developed a five-point model of BZ conformational similarity to the endogenous transporter ligand, L-T3: the alkyl substitution at the N1 of the BZ ring seems to simulate the alanine side chain of T3, and the electro-negative halogen and oxygen atoms of substituents at R3/R7/R2'/R4' of BZ form a pyramidal pharmacophore that seems to correspond with the 3-l/5-l/3'-l/4'-OH substituents of T3, respectively. These points, suggesting a tilted cross-bow formation, may be sites for ligand interaction with the iodothyronine transporter.

Topics: Benzodiazepines; Biological Transport; Carcinoma, Hepatocellular; Cell Membrane; Humans; Image Processing, Computer-Assisted; Liver Neoplasms; Membrane Proteins; Models, Molecular; Structure-Activity Relationship; Thyronines; Thyroxine; Triiodothyronine; Tumor Cells, Cultured

Plasma triiodothyronine (T3), reverse T3 (rT3), thyroxine (T4), total thyroid hormone-binding globulin (TBG) capacity, and serum albumin were assayed in patients with early and advanced breast and colonic cancer and in healthy women. Plasma T3 levels were reduced in both breast cancer group, but were reduced only in colonic cancer patients with systemic metastases. Plasma rT3 was normal in early cancer, but increased in nine of 38 (24%) with advanced breast cancer and four of 17 (24%) with metastatic colonic cancer; in consequence their rT3/T3 ratios were elevated. Plasma T4 concentrations were normal in all patient groups. Plasma TBG capacity was reduced in breast cancer patients with systemic metastases and a similar tendency occurred in metastatic colonic cancer. Levels of TBG were positively correlated with the serum albumin values. These changes were associated particularly with liver metastases.

Topics: Adult; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Female; Humans; Liver Neoplasms; Middle Aged; Thyronines; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine

Cultured monkey hepatocarcinoma cells were incubated with [3',5'-125I] diiodo-L--thyronine and with [3,5-125I] diiodo-L-thyronine. In both instances monodeiodination as well as sulfoconjugation took place. [3.-125I] iodothyronine and [3',5'-125I] diiodothyronine were identified as metabolites of [3'-5'-125I]-L-thyroxine in the cells, but neither [3-125I]-iodothyronine nor [3,5-125I] diiodothyronine was detected after incubation of the cells with ]3,5-125I]-L-thyroxine. No products of diphenyl ether splitting were observed in the medium after incubation of the cells with either [3,5-125I] diiodo-L-thyronine or [3,5-125I]-L-thyroxine.

Topics: Animals; Cell Line; Diiodothyronines; Haplorhini; Liver Neoplasms; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Adrenal Gland Neoplasms; Animals; Carbon Isotopes; Computers; Dihydroxyphenylalanine; Isocarboxazid; Liver Neoplasms; Melanins; Melanoma; Mice; Pancreatic Neoplasms; Pargyline; Thyronines