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S Hoekstra

Publications and source records attributed to S Hoekstra.

7 recordsLinked to original sources
PubMed1996

Induction of liver cytochrome P-450 (CYP) 3A in male and female rats by a steroidal androgen receptor antagonist, zanoterone.

The cytochrome P-450 (CYP) mediated hydroxylation of testosterone to 6 beta-, 7 alpha-, and 16 alpha-hydroxytestosterone (b beta-, 7 alpha-, and 16 alpha-OHT) and the dealkylation of ethoxycoumarin to 7-hydroxycoumarin (ECOD) and ethoxyresorufin to resorufin (EROD) were used to probe changes in CYP monooxygenase activities in liver microsomes from rats treated with the androgen receptor antagonist, zanoterone (Z). Phenobarbital (PB) and beta-naphthoflavone (beta-NF) were used as comparators. There were sex-related differences in the constitutive CYP activities and in the responses of CYP activities to Z. The greatest effect of Z administration was on 6 beta-OHT activity: It was increased up to 5.2-fold in males and 13.9-fold in females (Z high dose). The effect was larger than the produced by PB or beta-NF (< or = threefold increases). Z (high dose), PB, and beta-NF increased ECOD to a similar extent, e.g., about 1.3-fold in males and 1.2-2.9-fold in females. beta-NF increased EROD (11.2-fold males, 6.2-fold females) more than PB (3.4- to 4.6-fold) or Z (1.3- to 1.7-fold). Since hydroxylation of testosterone at the 6 beta position in rats and humans is catalyzed primarily by CYP isoforms from the 3A subfamily, the increase in 6 beta-OHT suggests that Z induced CYP 3A activity. These findings were confirmed with Western immunoblots with probes for rat CYP 1A1, 2B1/2, 2E1, 3A, and 4A. Z produced a three-to fourfold increase in the 3A isoform for both male and female rats. Results from this study suggest that in a clinical setting, Z therapy has the potential to induce CYPs of the 3A subfamily and in so doing alter the metabolism and clearance of drugs that are substrates for the 3A subfamily.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1995

Inhibition of T lymphocyte activation by a novel p56lck tyrosine kinase inhibitor.

A new p56lck tyrosine kinase inhibitor WIN 61651 [1,4-dihydro-7-(4-methyl-1-piperizinyl)-1-(4-(4-methyl-1-piperi zinyl))phenyl- 4-oxo-3-quinolinecarboxamide) is described. WIN 61651, which is competitive with ATP, demonstrates selectivity for the lymphoid restricted tyrosine kinase p56lck over serine/threonine kinases, such as protein kinase C and protein kinase A, and over some other tyrosine kinases, including erbB2, epidermal growth factor receptor, and insulin receptor; however, it is equipotent for inhibition of p56lck and the platelet derived growth factor receptor tyrosine kinases. WIN 61651 inhibits p56lck activity in cell-free assays, tyrosine kinase activity in a T lymphocytic cell line, and T cell activation, as measured by IL-2 production by purified CD4 positive peripheral blood T lymphocytes and the mixed lymphocyte reaction. WIN 61651 constitutes a new tool for studies on the role for tyrosine kinases in lymphocyte function.

Antibodies↗
PubMed1990

Suppressive effect of glucose administration on the binding of prolactin by rat liver.

In an attempt to elucidate the physiologic role of the hepatic receptors for prolactin (PRL), we studied the effect of changes in diet on the specific binding of 125I-ovine prolactin (oPRL) by membranes from female rat liver. Specific binding of PRL (SBP) was decreased by over 50% in rats fed 15% glucose ad lib for 2 days, as compared with fasted rats (P less than .01), while serum PRL was similar in both groups. Feeding 20% glucose by tube decreased SBP significantly, but tube-feeding equicaloric amounts of fat or protein-amino acid solution did not. Glucose feeding did not decrease the specific binding of 125I-bovine growth hormone (bGH) to liver, or decrease SBP to membranes of nitrosomethylurea (NMU)-induced mammary carcinomas, indicating that the effect of glucose on hepatic SBP is selective. Administration of glucose decreased SBP significantly in adrenalectomized-ovariectomized rats, in adrenalectomized-chemically sympathectomized rats, and in hypophysectomized rats receiving replacement therapy, including bovine prolactin (bPRL), bGH, hydrocortisone, estrogen, and thyroid hormones. Thus, the effect of glucose is not mediated by a factor from the adrenals, ovaries, or pituitary, and probably not by catecholamines. Administration of insulin to fasted diabetic rats did not alter SBP. Infusion of glucagon for 1 day, at a rate that did not alter serum glucose, increased hepatic SBP 29% (P less than .01). Since glucose administration decreases plasma glucagon, we hypothesize that glucagon may contribute to the maintenance of the hepatic PRL receptors, and that the suppressive effect of glucose on hepatic SBP may be mediated at least in part by suppression of plasma glucagon.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1988

Effects of prolactin and growth hormone on tissue and serum carnitine in the rat.

Previous experimental observations have suggested to us that PRL and GH may be involved in regulating the metabolism of carnitine, a factor that plays a critically important role in fatty acid oxidation and ketogenesis. In the present study we administered bovine PRL (bPRL) or bovine GH (bGH) at a physiologic rate to hypophysectomized female rats for 2-3 days, and observed that bPRL caused a small (16%) increase (P less than 0.01), and bGH a 36% increase (P less than 0.01), in hepatic carnitine, bPRL decreased serum carnitine by 24% (P less than 0.05), and bPRL and bGH each increased the liver/serum carnitine ratio by 58% (P less than 0.01), suggesting that these hormones enhance the active uptake of carnitine from plasma. bPRL and bGH, alone or in combination, did not affect the carnitine content of cardiac or skeletal muscle, but in combination they increased the heart/serum and muscle/serum carnitine ratios by 45-76% (P less than 0.01), thus allowing maintenance of normal cardiac and skeletal muscle carnitine despite a decreased plasma level. In hypophysectomized male rats, bPRL did not affect liver or epididymal carnitine. We hypothesize that PRL and GH may play a role in the regulation of the carnitine concentration of female liver by enhancing hepatic uptake of carnitine from plasma, and through this mechanism may affect hepatic fatty acid oxidation and ketogenesis. The effect of lactogenic and somatogenic hormones on hepatic carnitine and ketogenesis could be of particular physiological importance in late pregnancy and during lactation.

Animals↗
PubMed1987

Evidence for the recycling nature of the fibronectin receptor of macrophages.

Plasma fibronectin (pFN) has been shown to mediate phagocytosis of several types of artificial particles and tissue debris by macrophages. In the present investigation some of the dynamic aspects of this receptor-mediated cellular process have been studied. Plasma fibronectin did not bind specifically to fibronectin (FN)-receptors of rat peritoneal macrophages at either 4 degrees C or 37 degrees C. On the other hand, pFN aggregated on the surface of gelatin-coated latex beads (gLtx) and 125I-labeled pFN covalently coupled to latex beads (pFN-Ltx) bound strongly to macrophages at both temperatures. Both of these particles were also internalized at 37 degrees C. Treatment of macrophages by chymotrypsin, thermolysin, or trypsin in a protein-free tissue culture medium did not affect either of the above reactions; however, pronase treatment strongly reduced both the binding and internalization of the pFN-coated particles. The pronase-treated macrophage monolayers in time regained their ability to bind and internalize pFN-gLtx when incubated in fresh tissue culture medium. Such recovery, however, did not take place when the medium contained cycloheximide. On the other hand, phagocytosis of pFN-gLtx was not affected directly by cycloheximide with untreated macrophages; this suggests that the FN-receptor recycles during sustained phagocytosis. This assumption was substantiated by the observations that some of the established lysosomotropic amines--i.e., chloroquine, dansylcadaverine, and dimethyldansylcadaverine--caused total inhibition of internalization without affecting the binding of particles to macrophages. Furthermore, chloroquine protected the FN-receptors against destruction by pronase. Together these results suggest that macrophage receptors for FN are protein, present both on the cell surface and intracellularly, and recycle between the plasma membrane and intracellular sites during phagocytosis.

Animals↗
PubMed1985

Suppressive effect of inflammation and other forms of stress on the binding of prolactin by rat liver.

We have found that in female rats a variety of stressful stimuli, including sc inflammation, skin incision, endotoxin injection, and cold exposure, cause a significant decrease (30-86%) in the capacity of the hepatic cell membranes to specifically bind [125I]ovine PRL. Stress-induced decrease in food intake was not a factor in these studies, as nourishment was given only by tube feeding. Neither sc inflammation nor cold exposure affected hepatic binding of [125I]insulin. Further, the induction of inflammation in lactating rats and rats bearing 7,12-dimethylbenz[a]anthracene-induced mammary carcinomas did not affect the binding of PRL by the lactating or malignant mammary tissue. The suppressive effect of inflammation on hepatic binding of PRL was demonstrable in adrenalectomized-ovariectomized rats, in hypophysectomized rats receiving hormone replacement, and in adrenalectomized rats that had undergone partial chemical sympathectomy. We conclude that sc inflammation, as well as other forms of stress, decreases hepatic binding of PRL, but does not affect hepatic binding of insulin or mammary binding of PRL. The decrease in hepatic PRL binding is not mediated by a hormone secreted by the adrenals, ovaries, or pituitary, or by catecholamines, but could be mediated by another plasma factor or by peripheral dopaminergic neurons. Stress-induced decrease in hepatic PRL binding, or a related decrease in the binding of other polypeptide hormones, could play a role in the physiological response to stress.

Adrenalectomy↗