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K Kontula

Publications and source records attributed to K Kontula.

176 records · Page 10Linked to original sources
PubMed1975

Progesterone-binding proteins: in vitro binding and biological activity of different steroidal ligands.

Progesterone-binding proteins from human, rabbit, sheep and guinea pig myometrial cytosol, all induced with oestradiol, as well as from pregnant guinea pig myometrium and plasma were investigated. The physico-chemical properties of the oestradiol-induced binding proteins were very similar in all the species studied. In all, 63 steroids were tested for their ability to compete with tritiated progesterone for the binding sites on these six proteins and their relative affinities were determined. The studies reveal that the ligand specificities of oestrogen-induced myometrial binding proteins from human, rabbit and sheep are rather similar, whereas that from guinea pig myometrium has different binding characteristics. The properties of the binding proteins from pregnant guinea pig uterus and plasma differ substantially from all of the induced proteins. It is clear from the different physico-chemical characteristics and binding specificities that the oestrogen-induced myometrial protein of the guinea pig is not the same as that which appears in the myometrium and plasma during pregnancy. The binding energies of the well bound progestational compounds were of the order of -12 Kcal/mole, half of which stems from the interaction of the steroid nucleus with the protein. The specific interaction of the protein with the two functional groups, the 3-keto-4-ene system and the acetyl sid chain each contributed-3 Kcal/mole. In the case of the rabbit, sheep and human proteins a 17alpha-ethynyl-17beta-hydroxyl function could replace the acetyl side chain. For a large number of steroids reasonable agreement existed between the degree of binding to the rabbit myometrial protein and in vivo biological activity (Clauberg-McPhail test) in the same species. The data suggest that as far asthe binding aspect is concerned, the rabbit is an appropriate model for assessing the biological activity of compounds under development for human application. The in vitro binding system is also a useful tool to assess whether steroids need to be bio-activated before eliciting a biological response.

Aged↗
PubMed1975

Progesterone-binding proteins from endometrium and myometrium of sheep uterus: a comparative study.

The binding of tritiated proesterone to the cytoplasmic progestogen receptors from oestrogen-primed sheep endometrium and myometrium has been investigated. The binding characteristics of the progesterone receptors from both sources were determined in the supernatant fractions obtained after high speed centrifugation of the myometrial and endometrial homogenates. High affinity binding proteins with identical association constants for progesterone (1 times 10-9 M-1) were detected in both endometrium and myometrium. The concentration of binding sites was also of the same order of magnitude in both tissues. After centrifugation on surcrose gradients, these binding proteins were shown to have similar sedimentation constants, 7S in a gradient containing no added KC1 and 4S in a gradient containing 0.4 M KC1. The binding peaks from both sources could be abolished by heating the cytosol at 60 degrees C for half an hour. The proteinaceous nature of the binding materials was demonstrated by incubation of the endometrial and myometrial cytosols with pronase, DNase and RNase: the binding was totally eliminated by the proteolytic action of pronase whereas DNase and RNase had no effect. The ligand specificity of the two progesterone binding proteins was studied using a competitive protein-binding technique. Both the endometrial and the myometrial receptor proteins were shown to bind only steroids which are known potent progestogens. In addition, the relative affinities of the binding proteins for 37 steroidal compounds closely resembled each other. Thus, the physiochemical and binding data obtained show that a very close similarity exists between the progesterone-binding proteins in the endometrium and myometrium of ovariectomized sheep after oestradiol treatment.

Animals↗
PubMed1975

Steroid binding properties of estradiol receptors in human breast cancer.

The incidence of a specific estradiol receptor among the Finnish breast cancer patients was investigated using methods involving dextran-coated charcoal or sucrose density gradient centrifugation techniques. An estradiol receptor was detected in 20 (71%) out of the 28 tumor specimens studied with the following binding site concentrations: 100-1000 fmoles/mg cytosol protein in 12 patients; 10-99 fmoles/mg cytosol protein in 6 patients and below 10 fmoles/mg cytosol protein in 2 patients the lowest detectable level being about 5 fmoles/mg cytosol protein. The apparent intrinsic association constant of the receptor for estradiol-17 beta ranged from 0.4-32 X 10(10) liters/mole in different breast cancer specimens. Estradiol receptor concentration did not seem to correlate well with the age of the patients or the microscopic structure of the tumor. The ligand-binding specificity of the receptor was studied with 25 different estrogen derivatives in 6 separate tumor specimens. The binding proteins in all these tumors showed very similar ligand specificities, despite differences in their histological types and estradiol-binding site concentrations. The phenolic hydroxyl group at C--3 was essential for an effective binding by the receptor, whereas certain modifications in the D-ring structure were well tolerated. As is the case with other steroid receptors, certain hydrophobic substituents seemed to increase the binding of the ligand by the breast cancer estradiol receptor. The in vitro binding affinity and the in vivo biological (estrogenic) potency of some of the steroids investigated did not correlate very well.

Adsorption↗
PubMedDate not supplied

APOE alleles in Alzheimer's disease and vascular dementia in a population aged 85+.

Apolipoprotein E genotyping was carried out in a stratified random sample of 52 patients with Alzheimer's disease, 48 patients with vascular or mixed dementia, and 49 nondemented controls in a population-based study of people aged 85 and older (the Vantaa 85+ Study). Our results indicate that the apolipoprotein E epsilon 4 allele is associated with approximately a twofold increase in clinically diagnosed Alzheimer's disease in this very old general population aged 85+. When combined with previous studies, our data also suggest that the association is decreasing with age. In contrast, there appears to be no relation between apolipoprotein E alleles and clinically diagnosed vascular dementia.

Aged↗
PubMedDate not supplied

Testing of human homologues of murine obesity genes as candidate regions in Finnish obese sib pairs.

The human homologues of recently discovered murine obesity genes provide relevant candidates to study the genetic component of obesity in humans. We analysed the human counterparts to murine obesity genes ob, db, agouti, tub, melanocortin 4-receptor (MC4-R) and mitochondrial uncoupling proteins 2 and 3 (UCP2 and UCP3), as well as two other chromosomal regions reported to be linked to obesity-related phenotypes in restricted populations. We found no significant evidence for linkage to any analysed loci in our total study material of 105 affected sib pairs collected from the genetically homogenous population of Finland. However, several markers on 14 cM chromosomal region flanking the MC4-R gene showed sharing of alleles identical-by-descent (IBD) more frequently than expected. A selected subset of non-diabetic obese sib pairs strengthened the P values down to 0.003 in this particular region. The smallest P value (P = 0.001) was obtained with a marker D18S487 in a subgroup containing only sib pairs with one lean and one obese parent. We therefore screened seven obese subjects included in our sib pair material for sequence changes in their MC4-R gene, but no mutations of apparent causal relationship were found. In conclusion, we could not find evidence for significant contribution of the chromosomal loci corresponding to the murine single gene obesity genes for human morbid obesity, but additional studies are still needed to clarify whether DNA alterations within or adjacent to the MC4-R gene play some role.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Serum low density lipoprotein cholesterol level and cholesterol absorption efficiency are influenced by apolipoprotein B and E polymorphism and by the FH-Helsinki mutation of the low density lipoprotein receptor gene in familial hypercholesterolemia.

The aim of the present study was to evaluate the effect of variation of different gene loci separately and in concert on lipid metabolism in heterozygous familial hypercholesterolemia (FH). We assayed a unique low density lipoprotein (LDL) receptor gene defect (designated as FH-Helsinki), the XbaI polymorphism of the apolipoprotein (apo) B, phenotypes of the apo E, and determined the levels of serum lipoproteins, the efficiency of cholesterol absorption, and the values for several parameters of cholesterol metabolism in 51 unrelated patients with heterozygous FH. The genetic parameters were distributed independently of each other. Gender distribution and the prevalence of coronary artery disease were similar in the different apo E phenotypes, in the apo B genotypes, and in patients with and without the FH-Helsinki mutation. However, the FH-Helsinki mutation was associated with an increased body mass index. Serum LDL cholesterol was significantly elevated in patients with the FH-Helsinki mutation and the apo B X2 allele. Apo E phenotypes were not related to serum lipids per se, but the highest serum LDL cholesterol levels were measured in patients with the FH-Helsinki gene, apo E4 phenotype, and at least one X2 allele. Patients with the FH-Helsinki mutation and apo E4 phenotype had the highest cholesterol absorption efficiency. Cholesterol absorption was not related to serum lipids or lipoproteins, but LDL cholesterol was most elevated in patients with the most efficient cholesterol absorption. We conclude that in FH, diverse genetic factors exert individual and additive influences on serum LDL cholesterol levels.

Adolescent↗