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Biomedical subjects

J Weisz

Publications and source records attributed to J Weisz.

At least 37 records · Page 2Linked to original sources
PubMed1994

The effect of monocular viewing on heartbeat discrimination.

In monocular viewing conditions, an activational imbalance between the cerebral hemispheres was assumed to develop, the direction of which depends on the side of the viewing eye. This assumption was based on the morphological differences between the nasal and the temporal hemiretinas and on physiological data. It was assumed that the hemisphere receiving visual information via the nasal optic fibers, that is, the hemisphere contralateral to the viewing eye, would be the more activated one. Because heartbeat perception is regarded as a predominantly right hemispheric function, it was predicted that during right hemispheric activation created by left monocular viewing heartbeat discrimination performance would be better than during left hemispheric activation created by right monocular viewing. This hypothesis was tested on 30 male right-handed university students who performed a Whitehead-type heartbeat discrimination task while viewing only with the left or with the right eye. Heartbeat perception was more accurate when viewing with the left eye. Additionally, respiratory manipulation during heartbeat discrimination improved performance on this task.

Adult↗
PubMed1994

Conversion of estrone to 2- and 4-hydroxyestrone by hamster kidney and liver microsomes: implications for the mechanism of estrogen-induced carcinogenesis.

As part of an ongoing investigation of the role of metabolic activation of estrogens in the genesis of cancers such as estrogen-induced renal tumors in hamsters, we have 1) determined steroid-17 beta-oxidoreductase activity of microsomes and cytosol prepared from hamster kidney and liver; 2) compared the rates of 2-, 4-, and 16 alpha-hydroxylations of estrone by microsomes from hamster kidney and liver; and 3) determined the rates of inactivation of 2- and 4-hydroxyestrone by catechol-O-methyltransferase from hamster kidney and by purified enzyme. Microsomal steroid-17 beta-oxidoreductase activity in hamster kidney and liver was low and favored the conversion of estrone to estradiol. Cytosolic steroid-17 beta-oxidoreductase activity was only barely detectable in both liver and kidney. Using hepatic microsomes, the rate of 2-hydroxylation of estrone was comparable to that found previously using estradiol as substrate, whereas 4-hydroxylation of estrone was double that of estradiol. Using renal microsomes, the rates of 2- and 4-hydroxylation of estrone were 10- to 20-fold higher than those with estradiol as substrate, and the ratio of 2- to 4-hydroxylation was about 2:1. Fadrozole hydrochloride was an equally good inhibitor of rates of 2- and 4-hydroxylation of estrone (20 microM) by hepatic microsomes (IC50, approximately 25 microM). Corresponding IC50 values with renal microsomes were less than 2 microM, and 2-hydroxylation of estrone was inhibited by Fadrozole hydrochloride up to 15% more than 4-hydroxylation. Treatment of hamsters with estradiol for 2 months decreased rates of 2- and 4-hydroxylation of estrone by renal microsomes by approximately 95%. The rate of conversion of estrone to 16 alpha-hydroxyestrone by hepatic microsomes was 10-20% that of 2-hydroxylation. Renal microsomes catalyzed 16 alpha-hydroxylation of estrone at an even lower rate (approximately 5% of that of 2-hydroxylation). Rates of O-methylation of 2- and 4-hydroxyestrone by hamster kidney cytosol were comparable to those of 2- and 4-hydroxyestradiol. In conclusion, conversion of estrone to its catechol metabolites by microsomes of hamster kidney, a target organ of estrogen-induced carcinogenesis, is quantitatively more important than the conversion to 16 alpha-hydroxyestrone. The findings are consistent with the postulated role of catechol estrogens generated in situ in estrone-induced carcinogenesis.

Animals↗
PubMed1993

Central inhibition of nitric oxide synthase preferentially augments release of oxytocin during dehydration.

Intracerebroventricular (i.c.v.) administration of NG-monomethyl-L-arginine monoacetate (NMMA; 500 micrograms; 402 mM) and NG-nitro-L-arginine methyl ester (NAME; 270 micrograms; 200 mM), inhibitors of nitric oxide synthase, enhanced the rise in oxytocin but not vasopressin levels in plasma of conscious rats following 24 h of water deprivation. This effect of NMMA occurred by 10 min after administration, reached its peak at 15 min and decreased by 20 min. Daily administration of lower doses (50 micrograms and 0.5 microgram/5 microliter, i.c.v.) of another inhibitor of nitric oxide synthase, NG-nitro-L-arginine, just before and after 24 h of water deprivation and in control animals treated similarly were without effect on either vasopressin or oxytocin levels. Nitric oxide, therefore, attenuates preferentially the release of oxytocin during dehydration.

Amino Acid Oxidoreductases↗
PubMed1993

Hemispheric preference and lateral eye movements evoked by bilateral visual stimuli.

This study investigated the relationship between the direction of lateral eye shifts evoked by bilateral visual stimulation, on the one hand, and verbal vs visuospatial performance, on the other. In males a negative correlation was found between verbal relative to spatial accuracy and the ratio of leftward eye movements. No such relationship was found in females. Additionally, in males body mass index was smaller for those who displayed a greater ratio of leftward eye movements. It was concluded that visually evoked lateral eye shifts might reflect hemispheric preference, similarly as lateral eye movements obtained during the widely used questioning procedure. However, the procedure used in this study for evoking lateral eye shifts seems to be free of some methodological problems of the traditional procedure and is more easy to standardize.

Adolescent↗
PubMed1992

The influence of monocular viewing on heart period variability.

Monocular viewing seems to differentially activate the cerebral hemispheres. Viewing with only one eye is accompanied by a relatively greater activation of the contralateral hemisphere. In this study heart periods were measured during binocular, left and right monocular viewing in 29 right-handed males. Power spectral analysis of heart period variability showed that the amount of heart rate fluctuations in the 0.07-0.13 Hz frequency range (the mid-frequency peak of the spectrum) depends on the viewing eye. Only viewing with the left eye produced a significant increase of the mid-frequency peak. It is known that sympathetic activity contributes strongly to the mid-frequency component of the heart rate. Therefore, it is concluded that the effects of left monocular viewing result in an increased sympathetic influence on the sinoatrial node.

Adolescent↗
PubMed1992

Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens.

Characterization of enzymes mediating the formation of catecholestrogens (CE) by hamster kidney is of importance because of the proposed role of CE in renal cancer induced in this species by estrogens. We have reexamined the potential of hamster kidney to convert estradiol (E2) to 2- and 4-hydroxylated CE because of recent evidence of the limitations of assays used in previous studies, in particular in measuring 4-hydroxylation of estrogens. Under conditions optimized for NADPH-dependent activity, hamster kidney microsomes exhibited high levels of both E2-2- and E2-4-hydroxylase activities. Evidence that the two activities depend on different forms of cytochrome P-450 was obtained by the demonstration that 2- and 4-hydroxylation of E2 were affected differentially 1) by chronic treatment of hamsters with E2 and 2) by fadrozole hydrochloride, a selective cytochrome P-450 inhibitor. NADPH-dependent 2-hydroxylation of E2 from control and E2-treated hamsters, measured by a direct product isolation assay, was 1 order of magnitude higher (apparent maximum velocity, 24-32 and 6-12.5 pmol/mg protein.min in control and E2-treated hamsters, respectively) than that reported previously using radioenzymatic assays. NADPH-dependent 4-hydroxylation of E2 in controls approached and in E2-treated hamsters exceeded 2-hydroxylation of E2 (apparent maximum velocity, 17-21 and 7.5-19 pmol/mg protein.min in control and E2-treated hamsters, respectively). Thus, estrogen treatment reversed the ratios of NADPH-dependent E2-2-/4-hydroxylase activities by causing a much greater decline in 2- than 4-hydroxylation of E2 (P less than 0.007, by analysis of variance). Fadrozole hydrochloride caused a marked dose-dependent decrease in 2-hydroxylation of E2, in contrast to a small nondose-dependent inhibition of 4-hydroxylation. Under conditions optimized for peroxidatic organic hydroperoxide-dependent activity, hamster kidney microsomes generated 2- and 4-hydroxylated CE in similar amounts. The amounts of the two CE and, consequently, the ratios remained unaffected by estrogen treatment (1:0.9 and 1:1.0 in control and E2-treated hamsters, respectively). Thus, this study establishes that CE can be generated in the same tissue by three different pathways, i.e. NADPH-dependent E2-2-hydroxylase, NADPH-dependent E2-4-hydroxylase, and organic hydroperoxide-dependent E2-2/4-hydroxylase activities. We also show that these three activities can be regulated differentially and are, thus, probably mediated by different forms of cytochrome P-450. In hamster kidney, the potential to generate 4-hydroxylated CE metabolites with distinct properties could be a factor in this tissue's vulnerability to estrogen-induced carcinogenesis.

Animals↗
PubMed1990

Effect of chronic estrogen treatment of Syrian hamsters on microsomal enzymes mediating formation of catecholestrogens and their redox cycling: implications for carcinogenesis.

Estrogens have previously been shown to induce DNA damage in Syrian hamster kidney, a target organ of estrogen-induced cancer. The biochemical mechanism of DNA adduction has been postulated to involve free radicals generated by redox cycling of estrogens. As part of an examination of this postulate, we measured the effect of chronic estrogen treatment of hamsters on renal microsomal enzymes mediating catechol estrogen formation and free radical generation by redox cycling of catechol estrogens. In addition, the activities of the same enzymes were assayed in liver in which tumors do not develop under these conditions. At saturating substrate concentration, 2- and 4-hydroxyestradiol were formed in approximately equal amounts (26 and 28 pmol/mg protein/min, respectively), which is 1-2 orders of magnitude higher than reported previously. Estradiol treatment for 2 months decreased 2-hydroxylase activity per mg protein by 75% and 4-hydroxylase activity by 25%. Hepatic 2- and 4-hydroxylase activities were 1256 and 250 pmol/mg protein/min, respectively. Estrogen treatment decreased both activities by 40-60%. Basal peroxidatic activity of cytochrome P-450, the enzyme which oxidizes estrogen hydroquinones to quinones in the redox cycle, was 2.5-fold higher in liver than in kidney and did not change with estrogen treatment. However, when normalized for specific content of cytochrome P-450 the enzyme activity in kidney was 2.5-fold higher than in liver and increased further by 2-3-fold with chronic estrogen treatment. The activity of cytochrome P-450 reductase, which reduces quinones to hydroquinones in the estrogen redox cycle, was 6-fold higher in liver than in kidney of both control and estrogen-treated animals. When normalized for cytochrome P-450, the activity of this enzyme was similar in liver and kidney, but over 4-fold higher in kidney than liver after estrogen treatment. Basal concentrations of superoxide, a product of redox cycling, were 2-fold higher in liver than in kidney. Estrogen treatment did not affect this parameter in liver, but increased it in kidney by 40%. These data provide evidence for a preferential preservation of enzymes involved in estrogen activation.

Animals↗
PubMed1990

Hemispheric preference and obesity.

This study investigated the relationship of hemispheric preference--the tendency to activate one hemisphere rather than the other--and obesity, on 37 right-handed, male university students. Hemispheric preference was assessed by the directionality of conjugate lateral eye movements, and the degree of obesity was determined by the body mass index (BMI). The results showed that right hemisphere preferent subjects ("left-movers") are less obese than left hemisphere preferents ("right-movers").

Adolescent↗
PubMed1990

Hepatic catecholestrogen synthases: differential effect of sex, inducers of cytochromes P-450 and of antibody to the glucocorticoid inducible cytochrome P-450 on NADPH-dependent estrogen-2-hydroxylase and on organic hydroperoxide-dependent estrogen-2/4-hydroxylase activity of rat hepatic microsomes.

Formation of catecholestrogens (CE) by rat hepatic microsomes was re-examined because as recently shown; (1) CE formation can be catalyzed by an NADPH-dependent estrogen-4-hydroxylase (E-4-H(NADPH)) and by a peroxidatic, organic hydroperoxide-dependent estrogen-2/4-hydroxylase (E-2/4-H(OHP)), in addition to the established NADPH-dependent estrogen 2-hydroxylase (E-2-H(NADPH)); and (2) the indirect radiometric and the COMT-coupled radioenzymatic assays, used in many previous studies, may fail to provide an accurate measure, in particular, of 4-OH-CE. Using a direct product isolation assay, hepatic microsomes of both male and female rats were shown to express E-2/4-H(OHP) activity with properties similar to those of peroxidatic activity in other tissues. The activities of E-2/4-H(OHP) and E-2-H(NADPH) were affected differently by 5 out of 7 inducers of cytochromes P-450 administered in vivo. Phenobarbital and dexamethasone caused a 4- and 2-3-fold increase in E-2-H(NADPH) activity, respectively, but only a 38 and 20% increase in E-2/4-H(OHP) activity. Ketoconazol and beta-naphtoflavone caused a modest increase in E-2-H(NADPH) activity but a decrease in OHP-dependent activity. Clofibrate decreased peroxidatic activity by 50% and NADPH-dependent activity by approximately 20%. Both activities were increased by ethanol but decreased by isoniazide, an agent which induces the same form of cytochromes P-450 as ethanol. Polyclonal antibody against P-450p, a form of P-450 induced by glucocorticoids, inhibited E-2-H(NADPH) but not E-2/4-H(OHP) activity of untreated and of dexamethasone- and phenobarbital-treated rats. This study establishes that CE formation may occur in liver via the peroxidatic pathway and indicates that this pathway depends on forms of P-450 different from those mediating E-2-H(NADPH) activity. It also confirms and extends previous observations of the involvement of multiple, constitutive and induced forms of cytochrome P-450 in NADPH-dependent 2-hydroxylation in liver.

Animals↗
PubMed1990

The O-methylation of 4-hydroxyestradiol is inhibited by 2-hydroxyestradiol: implications for estrogen-induced carcinogenesis.

O-Methylation of catecholestrogens catalyzed by catechol-O-methyltransferase provides a major route for the rapid metabolic clearance of these steroids. However, the metabolic clearance rate of 4-hydroxyestradiol (4-OH-E2) is considerably lower than that of 2-hydroxyestradiol, although 2- and 4-hydroxycatecholestrogens (2- and 4-OH-CE) have similar apparent affinities for the enzyme. To determine the reason for this apparent paradox we have examined whether the efficiency of O-methylation of 4-OH-E2 could be affected by other catecholestrogens or their O-methyl ethers. The ratio of 4-methoxyestradiol:4-hydroxyestradiol 3-methyl ether was 2.6 at pH 8.5, the pH optimum for the reaction. The O-methylation of 4-OH-E2 (apparent Km 10 microM) was inhibited by 2-hydroxyestradiol (2-OH-E2) but not by 2- or 4-methyoxyestrogens. The values for Km, Vmax as well as the slope for the methylation of 4-OH-E2 were altered by 2-OH-E2 indicating a mixed inhibition. The inhibition constant for the intercept 1/V'max versus 2-OH-E2 concentrations and the inhibition constant for the slope versus 2-OH-E2 concentrations were 35 and 5.7 microM, respectively. The inhibition of O-methylation of 4-OH-E2 by 2-OH-E2 increased with the pH. In target tissues of the carcinogenic action of estrogens such as the rat pituitary, hamster kidney, or mouse uterus in which 2- and 4-OH-CE are both generated in almost equal amounts, the inactivation of 4-OH-CE by O-methylation may be impeded. Consequently, 4-OH-E2 would remain available as substrate for redox cycling, generation of active radicals and DNA damage.

Animals↗
PubMed1990

The effect of lateral visual fixation and the direction of eye movements on heartbeat discrimination.

This study was undertaken to determine whether the asymmetrical activation of the two cerebral hemispheres affects the accuracy of heartbeat perception. Hemispheric preference--the tendency to activate one hemisphere rather than the other--was assessed by the directionality of conjugate lateral eye movements. Actual differential hemispheric activation was achieved by contralateral visual fixation. The results of 44 right-handed male subjects showed that right hemisphere preferent subjects ("left-movers") performed better on a heartbeat discrimination task than left hemisphere preferent subjects ("right-movers"). The direction of lateral visual fixation also influenced heartbeat discrimination: subjects fixating to the left were more accurate than those fixating to the right.

Adolescent↗
PubMed1990

Naltrexone normalizes the suppression but not the surge of delta 5-3 beta-hydroxysteroid dehydrogenase activity in Leydig cells of stressed rat fetuses.

Rat fetuses from mothers stressed chronically by immobilization and high intensity illumination beginning on day 14 of gestation have higher than normal levels of delta 5-3 beta-hydroxysteroid dehydrogenase (3 beta HSD) activity in Leydig cells on day 17 of gestation and lower than normal levels on days 18 and 19. Plasma testosterone titers in normal and stressed male fetuses closely parallel the activity of 3 beta HSD in fetal Leydig cells. In the present study quantitative cytochemistry was used to determine whether the stress-induced alterations in 3 beta HSD activity could be prevented by treating the mother with naltrexone, an opioid receptor blocker, before each stress session. Naltrexone normalized 3 beta HSD activity on days 18 and 19 of gestation, suggesting that the stress-induced suppression involves the endogenous opioid system. In contrast, naltrexone did not prevent the elevation in enzyme activity seen on day 17 in stressed fetuses. The persistence of a stress-induced surge on day 17, in spite of naltrexone therapy, suggests that some nonopioid mechanism is operational at that time.

3-Hydroxysteroid Dehydrogenases↗
PubMed1989

Atrial natriuretic peptide in heart and specific binding in organs from fetal and newborn rats.

To assess the possibility that atrial natriuretic peptide plays a role in salt and water balance during early mammalian development, we examined hearts from fetal and neonatal rates for the presence of this peptide and presumed target tissues for their ability to bind the hormone. Immunohistochemistry was used to localize and radioimmunoassay to quantify this peptide in heart. Immunoreactive atrial natriuretic peptide was visualized in the fetal heart on day 17.5 post-conception. It was distributed throughout the atrial appendages and free wall and, in ventricle, in the trabeculae carnae and chordae tendineae. The concentrations of immunoreactive atrial natriuretic peptide in atria of rats on day 19.5 post-conception were one-tenth of those in the adult. Levels of this peptide in fetal ventricle were low and virtually absent from the adult tissue. Specific binding of radiolabelled atrial natriuretic peptide measured by whole organ counting occurred in several organs from 19.5-day fetal and neonatal rats. A number of these tissues, including the kidney, ileum, adrenal, lung and liver, are targets for and/or bind the peptide in adult rats. Specific binding in these tissues was localized using autoradiography at anatomical sites similar to those in adult organs. Specific binding was also seen in fetal but not neonatal skin. In the kidney, binding was associated with immature as well as mature glomeruli. These findings support the proposition that atrial natriuretic peptide may function in the perinatal rat as it does in the adult and, in addition, may play a unique role during fetal life.

Adrenal Glands↗
PubMed1989

Comparison of assays for catechol estrogen synthase activity: product isolation vs radioenzymatic catechol-O-methyltransferase-coupled procedures.

Reported values for the activity of enzymes mediating catechol estrogen formation by hamster kidney and liver, measured by catechol-O-methyltransferase-coupled radioenzymatic assay, have been uniformly low and there have been marked discrepancies in values reported from different laboratories. Therefore, we examined the validity of the radioenzymatic assay used in these studies. NADPH-dependent estrogen 2- and 4-hydroxylase activity of hamster liver microsomes measured by radioenzymatic assay was comparable to that reported in the literature but at least one order of magnitude lower than that obtained with a direct product isolation assay. Several features of the radioenzymatic assay were identified which, together, contribute to the underestimation of enzyme activity. They include, incomplete protection from oxidative degradation of both the catechol estrogens generated and of the catechol-O-methyltransferase and assay conditions which are suboptimal for O-methylation of the catechol estrogens. We conclude that results obtained using the catechol-O-methyltransferase-based radioenzymatic assay can only be considered valid if a consistent stoichiometric relationship can be demonstrated between the amounts of catechol estrogens and their O-methylated products.

Animals↗
PubMed1989

Plasma luteinizing hormone levels in normal and prenatally stressed male and female rat fetuses and their mothers.

Concentrations of luteinizing hormone (LH) were measured in plasma of fetal and neonatal rats obtained from control mothers and from mothers exposed to stress from Days 14 to 21 of gestation. The regimen of stress used is known to be associated with an abnormal ontogenetic pattern of testosterone secretion from the fetal testes. The overall ontogenetic pattern of immunoreactive LH levels in plasma was similar in male and female rats, and was unaffected by stress. In all groups, LH was low from Days 16 to 20 of gestation, and then rose progressively through birth, i.e. Day 23. However, stressing the mother significantly decreased the already low levels of LH between Days 16 and 20, as indicated by a larger percentage of samples from stressed fetuses of both sexes with LH levels below the limit of sensitivity of the assay. Sex differences in both the control and stressed group became evident only after Day 20 of gestation, with plasma concentrations of females exceeding those of males from Day 21 to 23 post-conception.

Analysis of Variance↗
PubMed1989

Monooxygenase mediating catecholestrogen formation by rat anterior pituitary is an estrogen-4-hydroxylase.

Microsomes from rat anterior pituitaries (AP) were incubated with (3H)estradiol under conditions previously shown to support catecholestrogen (CE) formation by placental microsomes via an NADPH- or an organic hydroperoxide-dependent, peroxidatic mechanism. Under conditions optimized for monooxygenase activity (pH 8.0, 5 mM NADPH), 4-hydroxylation predominated (apparent Vmax = 65 pmol and 13 pmol/mg protein/30 min for 4- and 2-hydroxy-E2, respectively). Under conditions optimized for peroxidatic activity (pH 6.0, 50 mM cumene hydroperoxide) 2- and 4-hydroxylated-E2 were produced in similar amounts. Thus in the AP, unlike in other target tissues studied, NADPH-dependent CE synthetase is a 4-hydroxylase and significant 2-hydroxylation occurs only via the peroxidatic mechanism. We propose that 4-hydroxylated CEs, which are both potent, long acting estrogens and catechols, serve as local mediators of actions of phenolic estrogens on the AP.

Animals↗
PubMed1988

Steroid structure and function. Molecular conformation of 4-hydroxyestradiol and its relation to other catechol estrogens.

Hydroxylation of estrogens at C(2) or C(4) effects differentially their binding affinity to and dissociation rate from the estrogen receptor. The X-ray crystal structure of 4-hydroxyestradiol (4-OH-E2) is reported here and compared with that of 2-hydroxyestradiol (2-OH-E2), the 2- and 4-hydroxylated derivatives of estrone (E1) and with that of the parent estrogens, E1 and E2. The overall molecular shape and hydrogen bonding patterns of each were examined for their possible relevance to their binding to the estrogen receptor and their biological activity. A shift in the B-ring conformation away from the symmetrical 7 alpha,8 beta-half-chair form toward the 8 beta-sofa form is induced by both 2- and 4-hydroxy substitution. This shift appears to be larger in the case of E2 than E1 derivatives and to be correlated with an observed change in the hydrogen bonding potential of the C(3) hydroxyl. In 4-OH-E2, as in E2 and 4-OH-E1, the C(3) hydroxyl functions both as a hydrogen bond donor and acceptor. In contrast in 2-OH-E2 the hydroxyl functions only as a donor. The markedly reduced affinity of 2-hydroxylated estrogens for the estrogen receptor could be due to a combination of steric interactions, competition between O(2) and O(3) for hydrogen bonds for a common site on the receptor, and to general interference with hydrogen bond formation of O(3). The C(4) hydroxyl participates in the formation of a chain of hydrogen bonds in the solid state that is similar to a chain seen in single crystals of E2. The presence of a similar chain of hydrogen bonds involving O(3) in the receptor site could account for the decreased dissociation rate of the 4-OH-E2 receptor complex.

Crystallography↗