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Biomedical subjects

S Schenker

Publications and source records attributed to S Schenker.

At least 19 recordsLinked to original sources
PubMed1992

Human placental transfer of zinc: normal characteristics and role of ethanol.

The fetal alcohol syndrome is primarily an impairment of growth and development. Zinc deficiency also causes abnormal fetal growth. Moreover, alcohol has been shown in some rodent studies to impair placental transport of zinc. The purpose of this investigation was to define better normal human placental zinc transport and the effects of alcohol on this process. To do this we employed the isolated perfused single cotyledon human term placental model, as well as the cultured human cytotrophoblast. In the perfused placental studies, it was shown that zinc is transferred by the placenta very slowly, about 6% of the rate of transport of antipyrine, a freely diffusible marker. The transfer is comparable in both directions, maternal to fetal and the reverse. Zinc does not cross the placenta against a zinc concentration gradient, in either direction. Rather there is good evidence of significant uptake (storage) of the zinc by the placenta on the recirculating compartment side of gradient studies. Moreover, when the perfusion fluid was low (0.2 g/100 ml) in albumin, about twice as much zinc accumulated in the perfused cotyledon and there was less zinc in the maternal compartment, as compared to perfusion with ten-fold higher (2.0 g/100 ml) albumin concentrations. Thus, ligand binding in the perfusate importantly influences placental zinc uptake. Interestingly, however, the increased placental binding of zinc did not translate into greater transfer of zinc to the fetal compartment. Thus, normal zinc transfer is slow, equal bidirectionally, and dependent on ligand binding in perfusate and placenta.(ABSTRACT TRUNCATED AT 250 WORDS)

Culture Techniques↗
PubMed1992

Human placental vitamin B6 (pyridoxal) transport: normal characteristics and effects of ethanol.

The aims of this study were to define normal human placental transport of pyridoxal, an important form of vitamin B6 in pregnancy, and to determine the effect of short-term alcohol on this process. Our studies used the isolated single cotyledon from the term placenta. Pyridoxal crossed the human placenta readily in both directions, but the transfer was a little less than half that of antipyrine and was significantly greater in the direction of the fetus. Pyridoxine appeared to have a similar clearance from the maternal compartment as pyridoxal, but transport of intact pyridoxal 5'-phosphate was much smaller. There was no saturable transfer of pyridoxal, and it was not transferred from the maternal to fetal compartments against a concentration gradient. Placental concentration of pyridoxal exceeded both maternal and fetal perfusate pyridoxal concentrations, but this concentration was equal for both perfusion directions. These composite data are most suggestive of passive transport of pyridoxal across the placenta, binding of the vitamin in the placenta as an explanation for its concentration there, and greater phosphorylation of pyridoxal in the placenta when the compound is transferred in the fetal direction, possibly displacing pyridoxal from its binding sites and permitting its greater release into the fetal compartment. Alcohol, 400-250 mg/dl over 2.5 h, inhibited the transport of pyridoxal from the maternal to fetal compartments by approximately 42% (P = 0.03) and resulted in a lower transfer of pyridoxal 5'-phosphate into the fetal perfusate (P = 0.02).

Biological Transport↗
PubMed1992

Acyclovir transport by the human placenta.

Genital Herpes simplex infection is noted increasingly in women of childbearing age and in neonates. Concern about transmission of herpes to the newborn has led to cesarean delivery of many pregnant women with a history of genital herpes. Severe herpes hepatitis has also been noted in pregnancy. Acyclovir is the drug of choice for this infectious organism. Because there are no data on the mechanism(s) of transport of this drug by the human placenta, this study addressed this issue. We used normal term human placentas. For study of overall placental transport of acyclovir, we used the single, isolated perfused cotyledon technique. For assessment of initial acyclovir uptake, we used microvesicles prepared from the maternal-facing syncytiotrophoblast. Overall transfer of acyclovir at therapeutic concentrations from maternal to fetal compartment was at a rate of about 30% that of a freely diffusible marker, antipyrine. The overall transport was not saturable, was not inhibited by 50-fold adenine concentration, and did not proceed against a concentration gradient. There was no placental metabolism of the drug. Fetal-to-maternal transfer of acyclovir was at a similar rate. In maternal-facing microvesicles net uptake of acyclovir was not saturable, but was temperature dependent and was inhibited by high concentrations of adenine and ganciclovir, but not by nucleosides (adenosine, cytidine, cytosine). These data are most consistent with a carrier-dependent, nucleobase-type uptake of the drug, but passive overall net transfer of acyclovir, dependent on its solubility characteristics.

Acyclovir↗
PubMed1991

Transforming growth factor beta 1 inhibits epidermal growth factor receptor endocytosis and down-regulation in cultured fetal rat hepatocytes.

Incubation of fetal rat hepatocytes (FRH) with transforming growth factor beta 1 (TGF-beta 1) resulted in growth arrest and a biphasic effect on epidermal growth factor (EGF) receptor. After 2 h of exposure, EGF receptor (EGFR) was reduced by 43%. From 6 to 24 h, TGF-beta 1 exposure resulted in progressive increase in EGFR up to 74% over control. The increased binding was due to increase in high affinity EGF binding sites. FRH grown in medium containing EGF exhibited down-regulated EGFR with loss of high affinity EGF binding sites. With TGF-beta 1 exposure, high affinity EGFR was not down-regulated by EGF. Since down-regulation of EGFR involves internalization, the kinetics of EGF receptor-mediated endocytosis were examined. In TGF-beta 1-exposed FRH, EGF endocytosis was inhibited, with a reduction in the first order rate constant for the process from 0.078 to 0.043 min-1. Despite inhibition of growth, receptor down-regulation, and EGF endocytosis after TGF-beta 1 exposure, EGF-induced receptor autophosphorylation was preserved as demonstrated by [32P]phosphate-labeling of immunoprecipitated EGFR. These observations provide direct evidence that TGF-beta 1 regulates growth of fetal cells. Further, they suggest that TGF-beta 1 regulates endocytosis of EGF and possibly of other ligands.

Animals↗
PubMed1991

Insignificant transfer of glyburide occurs across the human placenta.

No data exist concerning human placental transfer of oral hypoglycemic agents during pregnancy. This study characterizes the transport of glyburide in 10 term human placentas with the single-cotyledon placental model. Serial samples were taken from both the maternal and fetal reservoirs during each 3-hour perfusion, and the percent transport and metabolism of tritiated glyburide was calculated with liquid scintillation spectrometry and high-performance liquid chromatography. Antipyrine labeled with carbon 14 was added to the perfusate solution during these experiments as a control. Virtually no transfer of glyburide occurred, and no appreciable metabolism of the drug was detected. Neither variation in the albumin concentration nor increase in the maternal glyburide levels to 100 times therapeutic concentration materially altered the rate of transport. These data show that insignificant transport of glyburide occurs across the human placenta in vitro and suggest that fetal exposure to maternally administered glyburide likewise may be insignificant.

Diazepam↗
PubMed1991

Interactive effects of ethanol and caffeine on rat fetal hepatocyte replication and EGF receptor expression.

This study reports on the interactive effects of ethanol and caffeine on growth of rat fetal hepatocytes. Exposure of cultured rat fetal hepatocytes (RFH) to ethanol in concentrations above 1 mg/ml, causes a blockade of EGF-dependent cell replication along with an overexpression of surface EGF receptors (EGF-R). However, RFHs exposed for 24 hours to ethanol at a concentration of 1 mg/ml alone had little effect on cell replication. Caffeine, when combined with this concentration of alcohol, progressively impaired RFH growth by up to 100%. Caffeine alone up to 10 micrograms/ml, on the other hand, caused a progressive increase in RFH replication associated with a 69% enhancement of DNA synthesis. Caffeine concentrations in excess of 50 micrograms/ml had no effect on replicative capacity. Concomitant caffeine exposure had no effect on the ethanol-related increase in cell DNA content, yet it caused a further enhancement of the cell protein accural induced by ethanol alone. Caffeine (10 micrograms/ml) alone had no effect on EGF-R expression, while ethanol (2 mg/ml) increased it by almost 200%. Addition of caffeine to ethanol reduced this enhanced EGF binding by 45%. Scatchard analysis indicated that no treatment altered ligand affinity for the receptor, but that the alterations in binding caused by ethanol and the caffeine/ethanol combination reflected changes in binding capacity, in both low and high affinity components. It is concluded that (1) ethanol blocks EGF-mediated replication accompanied by a reduction in DNA synthesis, (2) caffeine alone at low concentrations has the opposite effect and can actually potentiate the EGF-mediated mitogenic response, (3) caffeine in combination with ethanol acts synergistically to reduce RFH replication.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Colchicine clearance is impaired in alcoholic cirrhosis.

Colchicine may have benefit in primary biliary cirrhosis and alcoholic liver disease. It is currently used in patients with impaired liver function, yet little is known about its elimination in such patients. Colchicine clearance in the rat is significantly impaired in various models of liver disease. To study this in human beings, colchicine pharmacokinetics were compared in normal subjects and patients with alcoholic cirrhosis. Colchicine clearance was impaired in the cirrhotic patients. Normal subjects had a mean clearance of 10.65 +/- 1.82 ml/min.kg, whereas cirrhotic patients had a mean clearance of 4.22 +/- 0.45 ml/min.kg (p less than 0.01). The half-life was 57.4 +/- 14.2 min in control subjects vs. 114.4 +/- 19.7 min in cirrhotic patients (p = 0.054). Volume of distribution was not different in the two groups (0.718 +/- 0.1 L/kg in control subjects; 0.716 +/- 0.158 L/kg in cirrhotic patients, p greater than 0.99). No correlation was seen between colchicine clearance and bilirubin, albumin, prothrombin time or Child-Pugh classification, but this may be the result of the small number of patients studied. Based on the values measured, it is estimated that colchicine steady state would change from an average 1.12 ng/ml in normal individuals to 2.82 ng/ml in the cirrhotic patients if 0.6 mg were taken every 12 hr. It is unknown whether this change would be clinically significant. These data show that cirrhosis impairs colchicine clearance and demonstrates that the liver is a major route of colchicine elimination.

Adult↗
PubMed1990

The effect of liver dysfunction on colchicine pharmacokinetics in the rat.

Recent work has shown that colchicine may benefit patients with primary biliary or alcoholic cirrhosis. However, very little is known about its pharmacokinetics in the presence of impaired liver function. To study this we examined the effects of three models of experimental liver dysfunction and one of cytochrome P-450 inhibition on colchicine elimination in the rat. The models of experimental liver dysfunction included bile duct ligation (with sham-operated controls), alpha-naphthylisothiocyanate-induced intrahepatic cholestasis and galactosamine-induced diffuse hepatocellular necrosis. The control group had a colchicine clearance of 77.33 ml/min.kg +/- 8.27 ml/min.kg, a half-life of 16.68 min +/- 0.97 min and a volume of distribution of 1.84 L/kg +/- 0.15 L/kg. Cimetidine administration, 120 mg/kg intraperitoneally 15 min before colchicine administration, caused clearance to decrease by 32% (p less than 0.05) and half-life to increase by 38% (p less than 0.05). Volume of distribution did not change. At 48 hr after bile duct ligation, colchicine clearance decreased by 84% (p less than 0.05), terminal half-life increased to 513.7 min +/- 106.6 min (p less than 0.05) and volume of distribution increased by 175% (p less than 0.05). Colchicine pharmacokinetics in sham-operated rats were not statistically different from the above mentioned controls.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Naphthylisothiocyanate↗
PubMed1990

Azidothymidine (zidovudine) transport by the human placenta.

The diagnosis of Acquired Immunodeficiency Syndrome (AIDS) is increasingly made in pregnant women, and the disease may be transmitted to the fetus. Azidothymidine (AZT, Zidovudine) is the one therapeutic agent of some promise in this condition. As there is no information on the transport of this drug by the human placenta, such studies were carried out using the single cotyledon placental perfusion system and human placental vesicles. AZT crossed the placenta readily and bidirectionally. The transfer rate was about 70% that of a freely diffusible reference marker, antipyrine, and was comparable in both directions. There was no evidence of active or carrier-mediated transport and no glucuronidated metabolites of the drug were identified in either maternal or fetal compartments. The authors believe that the drug crosses the placenta by diffusion, consistent with its lipophilicity and transport into various blood cells.

Antipyrine↗
PubMed1990

Thiamine-transfer by human placenta: normal transport and effects of ethanol.

Transport of "physiologic" concentrations of thiamine by the normal, term human placenta was studied by using the perfused cotyledon technique. Thiamine, 50 nmol/L, crossed from the maternal to fetal compartment at a rate somewhat below that of antipyrine, a freely diffusible marker drug. The transport was saturable and inhibited by structural analogues of thiamine, implying participation of carriers. Thiamine accumulated in the fetal compartment against a concentration gradient, suggesting active transport. Consistent with this, transfer of thiamine from the fetal to maternal compartment was significantly lower than in the opposite direction. The vitamin was concentrated in the placenta when compared with maternal and fetal levels. There was no evidence of phosphorylation of thiamine during its transfer. Exposure of the placenta to ethanol, 400 mg/dl, for up to 4 hours did not alter maternal-to-fetal transfer of the vitamin.

Antipyrine↗
PubMed1989

A model of cytochrome P-450-centered hepatic dysfunction in drug metabolism induced by cobalt-protoporphyrin administration.

Cobalt-protoporphyrin treatment disrupts cytochrome P-450-centered drug metabolism and is known to decrease significantly the cytochrome P-450 content of the liver. This study assesses further the correlations between biochemical and functional changes induced by Co-protoporphyrin. Specifically, it confirmed the fall in cytochrome P-450 levels in liver and demonstrated that both NADPH-cytochrome P-450 reductase and NADH-cytochrome b5 reductase activities decreased in a dose-dependent manner, albeit to a lesser degree, upon Co-protoporphyrin administration. Furthermore, plasma clearance of the marker drug aminopyrine fell off abruptly with a minimal decrease in cytochrome P-450 content, and then monotonically with its further depletion. Both aminopyrine and caffeine demethylation, as measured by the amount of radiolabeled CO2 exhaled, also decreased with diminishing cytochrome P-450 content. With aminopyrine the decrease was abrupt but with caffeine biphasic, consistent with preferential isozyme depletion. The drop in oxidative drug metabolism measured by these two in vivo techniques occurred in the absence of organellar damage to hepatocytes, as observed by electron microscopy. In vitro studies of aminopyrine metabolism in microsomes prepared from rats with and without Co-protoporphyrin injection proved to be consistent with the in vivo studies. Moreover aminopyrine Vmax decreased and Km increased with decreasing cytochrome P-450 content, suggesting preferential isozyme depletion. Furthermore, the changes in aminopyrine intrinsic clearance predicted by the in vitro Vmax and Km values agreed with those measured by in vivo plasma clearance. Taken together, these data suggest that Co-protoporphyrin treatment can be used to produce a model of altered cytochrome P-450-centered drug metabolism, as measured consistently by several techniques. However, this model appears to be more complex than one involving nonspecific depletion of cytochrome P-450 alone, and may be influenced also by concomitant changes in the electron transport chain or other aspects of hepatic metabolism.

Aminopyrine↗