Intravenous administration of alpha-galactosyl carbohydrates reduces in vivo baboon serum cytotoxicity to pig kidney cells and transplanted pig hearts.
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Animals↗
Biomedical subjects
G Koren
Publications and source records attributed to G Koren.
Biotransformation of carcinogenic arylamines and arylamides by human placenta.
Placental biotransformation reactions may modulate the effect a xenobiotic has on the developing fetus. However, in spite of the critical role the placenta plays in supporting fetal life, little is known about the pharmacology and toxicology of the human placenta. Our laboratory has previously characterized the N-acetylation activity of the human term placenta. This activity is predominantly attributable to the NAT1 form of arylamine N-acetyltransferase (NAT). Although acetylation is generally thought to be a detoxifying reaction, both N-acetylation and deacetylation reactions play an important role in the activation of carcinogenic arylamines to their reactive and toxic forms. In the current study we characterized the activity of human placental NAT and deacetylase toward the carcinogenic arylamine, 2-aminofluorene (AF) and its acetylated metabolite, 2-acetylaminofluorene (AAF). 2-Aminofluorene is a synthetic, prototype carcinogenic arylamine compound, and its metabolism has been extensively studied in the laboratory. Our data show that the affinity (Km = 24.2 +/- 1.66 mumol/L; mean +/- SEM, n = 6) and maximal velocity (Vmax = 4.29 +/- 0.33 nmol/min/mg; mean +/- SEM, n = 6) of AF N-acetylation by human placenta are similar to those in human liver. The deacetylation of AAF to AF by placental microsomes may be catalyzed by a carboxylesterase. However, our studies with inhibitors reveal that the characteristics of human placental deacetylation activity differ from that of human liver.(ABSTRACT TRUNCATED AT 250 WORDS)
2-Acetylaminofluorene↗
Safety of the new quinolones in pregnancy.
OBJECTIVE: To investigate the effect on the fetus of intrauterine exposure to quinolones in terms of teratogenicity, with special focus on the musculoskeletal system. METHODS: We studied 38 pregnant women who received quinolones and consulted the Motherisk Program in Toronto from 1989-1992. Perinatal complications, birth weight, birth defects, and developmental milestones, with particular emphasis on the musculoskeletal system, were compared with those of controls matched for both maternal age and indication for antibacterial therapy. RESULTS: Thirty-five women (92%) treated with norfloxacin or ciprofloxacin received therapy during the first trimester. The most common indication for therapy (92%) was urinary tract infection. More pregnancies in the quinolone group resulted in cesarean delivery due to reported fetal distress as compared to the controls (P = .005), without clear reason. Children born to mothers treated with quinolones were significantly heavier (P = .05) than the control infants, possibly because of better control of the urinary tract infection. No malformations were found in the quinolone group, whereas one child in the control group had a ventricular septal defect. No differences were detected between the groups in achievement of developmental milestones or in the musculoskeletal system. CONCLUSION: The use of the new quinolones during the first trimester of pregnancy does not appear to be associated with an increased risk of malformations or musculoskeletal problems; however, longer follow-up and magnetic resonance imaging of the joints may be warranted to exclude subtle cartilage and bone damage.
Abnormalities, Drug-Induced↗
Acetylcholinesterase and butyrylcholinesterase activity in the human term placenta: implications for fetal cocaine exposure.
The characterization of the enzymes responsible for drug metabolism in the human placenta is of great importance in determining the possible role the placenta plays in protecting the fetus from potentially fetotoxic drugs. We speculate that the placenta metabolizes cocaine, serving to protect the fetus from the drug's ill effects. Cholinesterase, the principle enzyme that metabolizes cocaine, has been hypothesized to be present yet is not well characterized in the human placenta. The purpose of this study was to quantify human placental acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity. Human placentas were obtained from elective cesarean sections, and several lobules were thoroughly perfused with cold buffer to ensure minimal contamination from erythrocyte AChE. Subcellular fractions were then prepared from these lobules by using standard differential centrifugation techniques. Microsomes and cytosol were assayed for AChE and BChE activity by using a spectrophotometric assay. BChE activity was found in the cytosolic fraction of the placental villous tissue, whereas AChE activity was measured in the microsomal fraction. By demonstrating that BChE activity is present in human term placenta we have shown that this organ has the capacity to metabolize cocaine and may therefore serve as a metabolic barrier to fetal exposure to cocaine.
Acetylcholinesterase↗
Recent increases in numbers and risk of fatalities in young children ingesting iron preparations.
Iron preparations are the most frequent cause of pediatric ingestion fatalities. The purpose of this study was to quantify the impression of an increase in iron deaths in young children and to postulate on the reasons. Using the data provided by the American Association of Poison Control Centers, overall annual mortality rate from iron preparations and among children < 6 y was calculated and changes in incidence were recorded. Between 1983 and 1991, there was a 2 to 3-fold increase in the numbers of reported ingestions of iron preparations by toddlers. In the general population the annual mortality rate/100 exposures to iron preparations increased from 0.05 during 1983-1990 to 0.116 in 1991 (p < 0.01). A similar trend was noted in children < 6 y with a rate of 0.004 in 1983-1990 compared with 0.12 in 1991 (p < 0.01). Hence, the increase in mortality was beyond what would be predicted from the increased number of ingestions noted. It is likely that increased awareness of pregnancy-induced anemia results in abundant use of iron pills. These pills have the appearance of candies, which should be changed immediately by legislation. During this period, the volume of iron preparations prescribed increased only marginally (16%), suggesting that over-the-counter use of iron pills increased substantially. In addition to warning labels and child-resistant packaging, an aggressive educational plan directed at the general population and physicians should be instituted immediately.
Child, Preschool↗
Arylamine N-acetyltransferase activity of the human placenta.
The fetus is exposed to almost all of the substances found in the maternal circulation whether nutrients or foreign chemicals ("xenobiotics"). The main route of exposure is the placenta. The placenta is metabolically active toward xenobiotics and the nature of the compounds reaching the fetal circulation will, in part, depend on placental biotransformation reactions. Arylamine N-acetyltransferase (NAT) catalyzes the acetyl CoA-dependent N-acetylation of primary arylamine and hydrazine substrates such as sulfamethazine, isoniazid, p-aminobenzoic acid as well as arylamine carcinogens such as 2-aminofluorene and benzidine. NAT activity is multigenically determined and can be attributed to two independently expressed proteins: NAT1 and NAT2. The acetylation capacity of the human placenta has not been investigated extensively. In the current study we identified and characterized the NAT activity of human term placenta. The kinetic data show that the activity of NAT in human placenta predominantly reflects the NAT1 enzyme. The apparent affinity (19.1 +/- 0.97 microM; mean +/- S.E.M., n = 22) and maximal velocity (3.84 +/- 0.32 nmol/min/mg; mean +/- S.E.M., n = 22) of p-aminobenzoic acid N-acetylation are similar to those measured in other tissues such as liver, blood lymphocytes, neutrophils and monocytes. In addition, there is evidence of NAT2 activity in some of the placental samples assayed, although the contribution of a small amount of NAT2 activity to the overall acetylation capacity of the placenta is likely to be small.
4-Aminobenzoic Acid↗
Human placental transfer and metabolism of p-aminobenzoic acid.
Studies in our laboratory have shown that the N-acetylation activity of the human term placenta is a predominantly attributable to the NAT1 form of arylamine N-acetyltransferase (NAT). To further assess the acetylation capacity of the placenta, the N-acetylation of the prototype NAT1-selective substrate, p-aminobenzoic acid (PABA), was studied using the in vitro human placental perfusion model. This study compared the net N-acetylation of PABA in intact placental tissue with the PABA acetylation activity observed in a subcellular fraction (cytosol). Such studies with intact tissue can permit assessment of the exposure of the fetus in vivo to drugs and their metabolites. Acetylated metabolite (N-acetyl-p-aminobenzoic acid) was detectable in fetal and maternal venous samples taken less than 5 min from the start of perfusion with PABA. In a closed recirculating system, the rate of placental PABA transfer decreased as PABA concentrations equilibrated across the placenta. In contrast, the rate of N-acetyl-p-aminobenzoic acid formation continued to increase throughout the entire time of perfusion. Kinetic parameters of PABA N-acetylation measured in cytosol prepared from perfused placental tissue show that the placenta retains its ability to N-acetylate PABA at fresh tissue levels even after 6 hr of in vitro perfusion (Vmax = 5.75 +/- 0.42 nmol/min/mg (fresh) vs. Vmax = 7.24 +/- 0.31 nmol/min/mg (perfused); mean +/- S.E.M., n = 6). These studies indicate that the human placenta has a significant capacity to N-acetylate NAT1-selective substrates of NAT and that it maintains its ability to metabolize xenobiotics during in vitro perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
4-Aminobenzoic Acid↗
In vitro assessment of the ethanol-induced hepatotoxicity on HepG2 cell line.
This study reports on measurement of the ethanol-induced hepatotoxicity in vitro on using the human hepatocyte cell line HepG2. Cells were incubated in the presence of increasing ethanol concentrations (10-80 mM). Cytotoxicity was quantitated spectrophotometrically both by the metabolism of the tetrazolium dye MTT and by the release into the medium of LDH and other marker enzymes of ethanol damage (AST, GGT and GHD). No cytotoxicity was observed up to 40 mM ethanol whereas a dose-dependent increment was found at higher concentrations (60-80 mM ethanol). At 80 mM ethanol, cell viability after 24 hours was reduced to 68% and 60% as assessed by MTT and LDH release respectively (p < 0.0001 vs. controls). Exposure for additional 24 hours did not increase cytotoxicity. Transmission electron microscopy revealed the presence of fat droplets (steatosis) and mitochondrial damage. The method reported appears to be an useful and reproducible technique for the in vitro assessment of the ethanol-induced cytotoxicity in a human liver cell line.
Analysis of Variance↗
The transcription of a mammalian voltage-gated potassium channel is regulated by cAMP in a cell-specific manner.
The transcript of Kv1.5, a Shaker-like delayed rectifier K+ channel cloned in our laboratory, is regulated in both tissue and developmentally specific manners. In this study we characterized the 5'-flanking region of the Kv1.5 gene. The gene lacks a canonical TATA box, has several transcription start sites, and the 5'-noncoding sequence is intronless. A cAMP response element (CRE) consensus signal was identified in the 5'-noncoding region. cAMP regulates the expression of Kv1.5 gene in a cell-specific manner. In primary cardiac cells, cAMP induces a 6-fold increase in the steady state levels of Kv1.5 transcript. However, in GH3 cells cAMP induces a 5-6-fold decrease in steady state levels of Kv1.5 transcript. The half-life of Kv1.5 transcript is 37 min and is not affected by cAMP. Nuclear run-on experiments show that in GH3 cells, cAMP reduces the transcription rate of Kv1.5 gene. Transient transfection assays using 5'-deletion mutations of Kv1.5 5'-flanking sequences revealed that the CRE located at +636 can confer the cAMP inducibility to Kv1.5 reporter gene constructs and binds to CRE-binding protein (CREB) and CRE modulator protein (CREM) in electromobility gel shift assays. Furthermore, KCl-induced depolarization can increase the steady state levels of Kv1.5 transcript in primary atrial cells and decrease it in GH3 cells. We conclude that cAMP and depolarization play an important role in regulating K+ channel expression and thus may induce long term effects on the pattern of electrical activity of excitable cells.
Animals↗
How women perceive teratogenic risk and what they do about it.
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Abnormalities, Drug-Induced↗
Measurements of the anisotropy and temperature dependence of the in-plane energy gap in YBa2Cu3O7- delta using Andreev reflections.
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Journal Article↗
Hair analysis as a marker for fetal exposure to maternal smoking.
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Adult↗
Evaluation and counseling of teratogenic risk: the motherisk approach.
The authors present a new approach for evaluation and counseling of teratogenic risk, The Motherisk program in Toronto presently deals with 60 inquiries per day from the public and health professionals. Most calls are answered through the telephone, and 16-20 women per week are scheduled for our clinic following exposure to known or suspected teratogens, to new drugs with sparse information, to chronic drug therapy, or drugs of abuse. Also seen in clinic are women who want to be counseled or whose physicians want them to meet us due to high levels of anxiety. Since its inception in 1985 the Program has been very effective in preventing unnecessary terminations of otherwise wanted pregnancies. In addition to the clinical service we followup the outcome of these prospectively collected exposures, thus creating a large data base necessary to verify safety/risk of various agents. During the last 2 years Motherisk has completed singly, or in collaboration, large prospective studies on gestational exposure to lithium, antiepileptics, cocaine, and fluexitime. To study the reproductive risks of cocaine we compared first-trimester exposure to cocaine with two control groups. Infants exposed to cocaine did not have higher rates of any adverse perinatal outcome. Their cognitive function at 18 months of age was identical to the control infants. Meta analysis of all studies assessing gestational risks of cocaine reveals that the results of these studies were dependent on the type of comparison conducted. When babies exposed to cocaine were compared with middle class nonusers, the cocaine groups seemed to be more often different from their controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Cocaine↗
Comparison of carboplatin pharmacokinetics between an anephric child and two children with normal renal function.
Carboplatin, a promising second generation platinum compound, is an effective antitumor drug and appears to be less nephrotoxic than cisplatin. We report comparative pharmacokinetics of carboplatin in an anephric child and two children with normal renal function. All three children were infused with carboplatin over 4 hours, the anephric child receiving 100 mg/m2 (25% of the dose received by the other two children). This dose was well tolerated and 18 days later the anephric patient received a second course of carboplatin at 50% of the regular dose received by the control patients. Following this dose the girl experienced severe pancytopenia and recovered with the use of GM-CSF, blood, and platelet transfusion. Blood samples were obtained at timed intervals for 24 hours in the control subjects and for 40 hours in the anephric patient. Plasma and plasma ultrafiltrates were analyzed for total and free platinum. The results show that elimination half-life of total platinum was 13 hours in the children with normal renal function and 42 hours in the anephric child following the 100 mg/m2 dose. The elimination T1/2 of free platinum was 8 hours in a child with normal GFR and 32 hours in the anephric child. In the anephric child the clearance of ultrafiltrable platinum was 10% of the normal total body clearance. We suggest that, in children with renal insufficiency, the dose of platinum derivatives should be carefully chosen, proportionally to the degree of renal impairment.
Blood Proteins↗
Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide.
A 29-year-old pregnant woman diagnosed with acute lymphocytic leukemia maintained remission with daily cyclophosphamide and intermittent prednisone treatment. She delivered a male twin with multiple congenital abnormalities who was diagnosed with papillary thyroid cancer at 11 years of age and stage III neuroblastoma at 14 years of age. The female twin was unaffected and has exhibited normal development to date. First trimester exposure to cyclophosphamide has been associated with major malformations. Metabolites of cyclophosphamide have been demonstrated to be teratogens and carcinogens in animals. Differences in placental or fetal hepatic cytochrome P-450 may account for the variability in response between the twins. In addition, disparity between the twins may be the result of differences in metabolite inactivating enzymes present either in fetal liver or placenta. The risk of second malignancies caused by alkylating agents such as cyclophosphamide has been well documented in adults and children but to the best of our knowledge this is the first description of transplacental second cancer.
Abnormalities, Drug-Induced↗
The mechanism of the verapamil-digoxin interaction in renal tubular cells (LLC-PK1).
Verapamil, usually given as a racemic mixture, decreases in vivo and in vitro digoxin renal tubular secretion, which is suggested to be mediated by P-glycoprotein, an ATP-dependent multidrug efflux pump. Importantly, the two enantiomers of verapamil have been reported to similarly inhibit P-glycoprotein-mediated transport of chemotherapeutic agents. In this study, we examined effects of enantiomers of verapamil on digoxin transport across an LLC-PK1 cell monolayer, a model of proximal renal tubular cells. The results indicate that verapamil inhibition of digoxin transport is non-stereospecific. Furthermore, the verapamil-digoxin interaction is not competitive. The two drugs may not share a common initial step in the P-glycoprotein-mediated transport.
Animals↗
P-glycoprotein-mediated renal tubular secretion of digoxin: the toxicological significance of the urine-blood barrier model.
We provide direct evidence that verapamil inhibits active digoxin secretion in renal tubular cells (LLC-PK1), and that verapamil increases cellular accumulation of digoxin. These findings suggest that verapamil inhibits the digoxin active secretory transport at the apical membranes, supporting the theory that P-glycoprotein mediates digoxin secretion in the renal tubular cells. Based on existing data on digoxin transport, we present a hypothetical model for the renal handling of digoxin, implying that P-glycoprotein functions as a driving mechanism of a unidirectional "urine-blood" barrier.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Morphine pharmacokinetics in children following cardiac surgery: effects of disease and inotropic support.
The pharmacokinetics of morphine have not been previously studied in children following cardiac surgery for tetralogy of Fallot (TOF) or transposition of the great arteries (TGA). Morphine steady-state pharmacokinetics were studied in 21 children undergoing repair of TOF, TGA, or atrio-ventricular septal defects (AVSD). Children with TOF or TGA had increased right-sided pressures with no differences between the groups. Children with TOF had significantly faster clearance rates of morphine (1.39 +/- 0.37 L/kg/h) than children following the Fontan procedure (0.86 +/- 0.31 L/kg/h, P < 0.01). When stratifying children by their postsurgical needs for inotropic support, those needing epinephrine, dopamine, or dobutamine at more than 10 micrograms/kg/min had significantly slower clearance rates (0.73 +/- 0.3 L/kg/h) when compared to the rest of the patients (1.5 +/- 0.41 L/kg/h, P < 0.05). Because most children needing inotropic support underwent the Fontan procedure, it is conceivable that their cardiovascular status had a major impact on morphine metabolism. These results suggest a 50% reduction in morphine dosage in children requiring inotropic support following cardiac surgery.
Blood Pressure↗