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Biomedical subjects

J D Huang

Publications and source records attributed to J D Huang.

At least 37 records · Page 2Linked to original sources
PubMed1997

Apolipoprotein B gene polymorphisms in Taiwanese ischemic stroke patients.

We analyzed the AluI restriction fragment length polymorphism (RFLP) of the apolipoprotein B (apoB) gene to determine the association between AluI allelic distribution and the occurrence of ischemic stroke in Taiwan. A total of 44 healthy volunteers and 159 ischemic stroke patients were included in the study. The allele frequency of AluI was very similar in the two groups, 0.87 in the patient group and 0.89 in the control group, for the major allele A-. The distribution of A-/A-, A-/A+, and A+/A+ genotypes of the patients was not significantly different from that of the controls. Among ischemic stroke patients, the A+ allele of the AluI restriction site was significantly associated with elevated apoB levels. The results of this study suggest that the presence of the rare AluI RFLP may contribute to an elevated plasma apoB level, which is a known risk factor for ischemic stroke.

Aged↗
PubMed1996

Formation of morphine from codeine in Chinese subjects of different CYP2D6 genotypes.

Codeine and morphine pharmacokinetics among different CYP2D6 genotypes was compared in this study. Polymerase chain reaction tests were used to determine CYP2D6 genotypes in leukocyte deoxyribonucleic acid in 32 unrelated volunteers. Based on the genotypes, subjects were categorized into three groups: homozygous C/C188 (n = 8), heterozygous C/T188 (n = 12), and homozygous T/T188 (n = 12). Each subject was given a single oral dose of 30 mg codeine phosphate tablet after overnight fasting. Plasma concentration of codeine and 24-hour urinary morphine recovery were measured with HPLC. All three genotypes of subjects showed almost identical time profiles of plasma codeine. Urinary morphine glucuronide was hydrolyzed with beta-glucuronidase. The total recovered amount of morphine and glucuronides was 4349 +/- 646, 2564 +/- 242, and 1127 +/- 164 nmol (mean +/- SEM), respectively, for C/C188, C/T188, and T/T188 subjects (p < 0.05). The significant lower amount of urinary morphine but identical codeine plasma concentration suggested a lower partial clearance of the formation of morphine from codeine in T/T188 subjects. The results suggest a future study to assess the analgesic effect of codeine in different genotypes of CYP2D6 extensive metabolizers.

Adult↗
PubMed1996

Nomenclature for human CYP2D6 alleles.

To standardize CYP2D6 allele nomenclature, and to conform with international human gene nomenclature guidelines, an alternative to the current arbitrary system is described. Based on recommendations for human genome nomenclature, we propose that alleles be designated by CYP2D6 followed by an asterisk and a combination of roman letters and arabic numerals distinct for each allele with the number specifying the key mutation and, where appropriate, a letter specifying additional mutations. Criteria for classification as a separate allele and protein nomenclature are also presented.

Alleles↗
PubMed1996

Inhibition of the intestinal digoxin absorption and exsorption by quinidine.

Digoxin-quinidine interaction is well documented in the literature. The mechanism is, however, unknown. Previously, it was shown that quinidine reduced digoxin secretion by inhibiting P-glycoprotein (Pgp) in the renal tubule. Because Pgp is expressed in the small intestine to an extent no less than that in the kidney, the study was designed to investigate the possible effect of quinidine on the absorption and exsorption of digoxin in the rat intestine. Results from the everted sac study using different Pgp inhibitors and inducers support that digoxin is a substrate of Pgp in both jejunum and ileum. Plasma concentration of digoxin after intravenous administration increased 2-fold when 1 mg/hr quinidine was coinfused, whereas the amount that appeared in the intestinal lumen decreased by approximately 40%. In the presence of quinidine, total clearance decreased from 318.0 +/- 19.3 to 167.1 +/- 11.0 ml/hr, whereas intestinal clearance decreased from 28.8 +/- 1.7 to 11.1 +/- 1.6 ml/hr. In a separate study, 3H-labeled digoxin was infused intravenously together with luminal perfusion of unlabeled digoxin in the intestine. The change of 3H-labeled digoxin concentrations in plasma and in the intestinal lumen was similar to those in the exsorption study. However, concentration of unlabeled digoxin in plasma or the intestinal lumen did not alter significantly with the addition of quinidine. The absorption clearance in the control group (N = 6, 6.4 +/- 0.47 ml/hr) was significantly higher than that in the group with quinidine coadministration (N = 6, 4.8 +/- 0.31 ml/hr; p < 0.05). This indicates that quinidine may affect not only the elimination of digoxin, such as renal secretion, but also the absorption/exsorption of digoxin in the gastrointestinal tract. This study suggests that Pgp is involved in the drug interaction between digoxin and quinidine in the small intestine. It is clinically important to understand the effect of quinidine on digoxin absorption for further assessment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Changes of propofol levels in isolated cardiopulmonary bypass circuit.

BACKGROUND: High dose fentanyl anesthesia in cardiac surgery has been supplemented with propofol to prevent patient's awareness and recall. It has been known that during cardiopulmonary bypass (CPB), fentanyl or midazolam concentration decreases, except for propofol where it remains unknown. This study evaluated the interaction between propofol and the CPB circuit in vitro. METHODS: Three identical experiments were conducted. In each experiment we used a set of CPB circuit composed of a standard 3/8 inch PVC tubing trap, a reservoir and a pump. The reservoir was primed with 2,000 ml solution of 2.5% dextrose and 0.45% NaCl in which 20 mg propofol was added. The solution was circulated in the circuit at a flow rate of 2 L/min. The experimental period was 30 min. A 5 ml sample of the solution was taken from the venous sampling site of the circuit immediately prior to the experiment, and thereafter each from the arterial and venous sampling sites at 1, 3, 5, 10, 20 and 30 min after the start of the experiment. The samples were kept at 4 degrees C and assayed by HPLC. RESULTS: The propofol concentrations decreased exponentially with the increase of experimental time. There were no significant differences in the concentrations and the rates of decrease between the arterial sampling site and the venous sampling site. The decrease was 20% at 1 min, 68% at 10 min, 83% at 20 min, and 92% at 30 min after the beginning of the experiment. CONCLUSIONS: The results demonstrate the presence of propofol sequestration by the CPB circuit. Evaporation in the bubble oxygenator, absorption by and/or adherence to the circuit are suspected as the possible causative factors.

Anesthetics, Intravenous↗
PubMed1995

The torso response element binds GAGA and NTF-1/Elf-1, and regulates tailless by relief of repression.

Modulation of transcription factor activity leading to changes in cell behavior (e.g., differentiation versus proliferation) is one of the critical outcomes of receptor tyrosine kinase (RTK) stimulation. In the early Drosophila embryo, activation of the torso (tor) RTK at the poles of the embryo activates a phosphorylation cascade that leads to the spatially specific transcription of the tailless (tll) gene. Our analysis of the tor response element (tor-RE) in the tll promoter indicates that the key activity modulated by the tor RTK pathway is a repressor present throughout the embryo. We have mapped the tor-RE to an 11-bp sequence; using this sequence as the basis for protein purification, we have determined that the proteins GAGA and NTF-1 (also known as Elf-1, product of the grainyhead gene) bind to the tor-RE. We demonstrate that NTF-1 can be phosphorylated by MAPK (mitogen-activated protein kinase), and that tll expression is expanded in embryos lacking maternal NTF-1 activity; these results make NTF-1 a likely target for modulation by the tor RTK pathway in vivo. The data presented here support a model in which activation of the tor RTK at the poles of the embryos leads to inactivation of the repressor and therefore, to transcriptional activation (by activators present throughout the embryo) of the tll gene at the poles of the embryo.

Animals↗
PubMed1995

Binding sites for transcription factor NTF-1/Elf-1 contribute to the ventral repression of decapentaplegic.

The Dorsal morphogen is a transcription factor that activates some genes and represses others to establish multiple domains of gene expression along the dorsal/ventral axis of the early Drosophila embryo. Repression by Dorsal appears to require accessory proteins that bind to corepression elements in Dorsal-dependent regulatory modules called ventral repression regions (VRRs). We have identified a corepression element in decapentaplegic (dpp), a zygotically active gene that is repressed by the Dorsal morphogen. This dpp repression element (DRE) is located within a previously identified VRR and close to essential Dorsal-binding sites. We have purified a factor from Drosophila embryo extracts that binds to the DRE but not to mutant forms of the DRE that fail to support efficient repression. This protein also binds to an apparently essential region in a VRR associated with the zerknüllt (zen) gene. One of the DREs in the dpp VRR overlaps the binding site for a potential activator protein suggesting that one mechanism of ventral repression may be the mutually exclusive binding of repressor and activator proteins. We have found the DRE-binding protein to be identical to NTF-1 (equivalent to Elf-1, the product of the grainyhead gene), a factor originally identified as an activator of the Ultrabithorax and Dopa decarboxylase promoters. NTF-1 mRNA is synthesized during oogenesis and deposited in the developing oocyte where it is available to contribute to ventral repression during early embryogenesis. Previous studies have shown that overexpression of NTF-1 in the postblastoderm embryo results in a phenotype that is consistent with a role for this factor in the repression of dpp later in embryogenesis.

Animals↗
PubMed1995

Enantioselectivity suggests a cytosolic origin for a commercial pig liver esterase preparation.

A widely utilized pig liver esterase preparation has been found to be derived essentially exclusively from the cytosolic fraction of pig livers. Esterases in cytosol and microsomes prepared from a fresh pig liver hydrolyzed the S- and R-enantiomers of racemic oxazepam 3-acetate (rac-OXA) with specific activity ratios of approximately 2.3:1 and 1:62, respectively. Product formations were analyzed by chiral stationary phase high-performance liquid chromatography. The commercial pig liver esterase preparation showed greater activity toward S-OXA than did the esterases in the cytosolic fraction prepared from fresh pig liver. The results established that (i) esterases contained in microsomes and cytosol of pig liver have opposite enantioselectivity in the hydrolysis of rac-OXA and (ii) the commercial pig liver esterase preparation has a cytosolic origin.

Animals↗
PubMed1995

Inhibition of intestinal P-glycoprotein and effects on etoposide absorption.

P-glycoprotein (Pgp) actively pumps a number of antineoplastic drugs, such as etoposide, out of cancer cells and causes multidrug resistance. Pgp is also expressed at the brush-border membrane of the small intestine under normal physiological conditions. We hypothesized that inhibition of intestinal Pgp might decrease the efflux of etoposide from the blood into the intestinal lumen, thereby, increasing the bioavailability of etoposide. The absorption of etoposide was studied using everted gut sacs prepared from rat jejunum and ileum. The addition of C219, a monoclonal antibody of Pgp, at 100 ng/ml or of 0.2 M 5'-adenylylimidodiphosphate, a nonhydrolyzable adenosine triphosphate (ATP) analog, increased the absorption of etoposide. Quinidine, an antiarrythmic agent, has been demonstrated to circumvent multidrug resistance in cell lines, possibly by interfering with Pgp function. Adding quinidine at 1 mg/ml to the everted gut sac increased the absorption of etoposide. In vivo absorption of etoposide was also studied by intraluminal perfusion of the drug in the small intestine of anesthetized rats. Intravenous infusion of quinidine at either 1 or 2 mg/h increased the serum level of etoposide in a dose-dependent manner. Intravenous infusion of etoposide at 0.2 mg/h resulted in luminal exsorption of the drug in the small intestine. The intestinal clearance of etoposide was 41.7 +/- 7.2 ml kg-1, which decreased to 18.4 +/- 3.9 ml kg-1 with the infusion of quinidine at 1 mg/h. The present data confirm that intestinal Pgp mediates the efflux of etoposide and that the use of Pgp-inhibiting agents such as quinidine may increase the bioavailability of etoposide.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1995

Propranolol disposition in Chinese subjects of different CYP2D6 genotypes.

Propranolol pharmacokinetics among different genotypes of CYP2D6 was compared in this study. The Chinese (Han) population consisted of 44 healthy unrelated individuals living in southern Taiwan. Endonuclease tests based on polymerase chain reaction were used to determine C/T188 genotypes of CYP2D6 in leukocyte deoxyribonucleic acid. Based on codon 188 genotypes, subjects were categorized into three groups: homozygous C/C188 (n = 13), heterozygous C/T188 (n = 14); and homozygous T/T188 (n = 17). Each subject was given a 40 mg propranolol tablet. Blood samples were drawn before and 12 hours after propranolol administration to measure propranolol and 4-hydroxypropranolol. Three genotypes showed distinct time profiles of plasma propranolol and 4-hydroxypropranolol. The area under plasma concentration curve values (mean +/- SEM), were 322.0 +/- 40.8, 481.6 +/- 77.5, and 766.1 +/- 92.8 nmol.hr/L, respectively, for C/C188, C/T188, and T/T188 subjects (p < 0.05). The 48-hour excreted amount of 4-hydroxy-S-propranolol-O-glucuronide, but not 4-hydroxy-R-propranolol-O-glucuronide, was significantly higher for C/C188 than for T/T188 subjects (p < 0.05). This study shows a different propranolol disposition in Chinese subjects of different CYP2D6 genotypes.

Adrenergic beta-Antagonists↗
PubMed1995

The decapentaplegic core promoter region plays an integral role in the spatial control of transcription.

The Drosophila melanogaster decapentaplegic (dpp) gene encodes a transforming growth factor beta-related cell signaling molecule that plays a critical role in dorsal/ventral pattern formation. The dpp expression pattern in the Drosophila embryo is dynamic, consisting of three phases. Phase I, in which dpp is expressed in a broad dorsal domain, depends on elements in the dpp second intron that interact with the Dorsal transcription factor to repress transcription ventrally. In contrast, phases II and III, in which dpp is expressed first in broad longitudinal stripes (phase II) and subsequently in narrow longitudinal stripes (phase III), depend on multiple independent elements in the dpp 5'-flanking region. Several aspects of the normal dpp expression pattern appear to depend on the unique properties of the dpp core promoter. For example, this core promoter (extending from -22 to +6) is able to direct a phase II expression pattern in the absence of additional upstream or downstream regulatory elements. In addition, a ventral-specific enhancer in the dpp 5'-flanking region that binds the Dorsal factor activates the heterologous hsp70 core promoter but not the dpp core promoter. Thus, the dpp core promoter region may contribute to spatially regulated transcription both by interacting directly with spatially restricted activators and by modifying the activity of proteins bound to enhancer elements.

Animals↗
PubMed1995

A genetic polymorphism in coumarin 7-hydroxylation: sequence of the human CYP2A genes and identification of variant CYP2A6 alleles.

A group of human cytochrome P450 genes encompassing the CYP2A, CYP2B, and CYP2F subfamilies were cloned and assembled into a 350-kb contig localized on the long arm of chromosome 19. Three complete CYP2A genes--CYP2A6, CYP2A7, and CYP2A13--plus two pseudogenes truncated after exon 5, were identified and sequenced. A variant CYP2A6 allele that differed from the corresponding CYP2A6 and CYP2A7 cDNAs previously sequenced was found and was designated CYP2A6v2. Sequence differences in the CYP2A6v2 gene are restricted to regions encompassing exons 3, 6, and 8, which bear sequence relatedness with the corresponding exons of the CYP2A7 gene, located downstream and centromeric of CYP2A6v2, suggesting recent gene-conversion events. The sequencing of all the CYP2A genes allowed the design of a PCR diagnostic test for the normal CYP2A6 allele, the CYP2A6v2 allele, and a variant--designated CYP2A6v1--that encodes an enzyme with a single inactivating amino acid change. These variant alleles were found in individuals who were deficient in their ability to metabolize the CYP2A6 probe drug coumarin. The allelic frequencies of CYP2A6v1 and CYP2A6v2 differed significantly between Caucasian, Asian, and African-American populations. These studies establish the existence of a new cytochrome P450 genetic polymorphism.

Alleles↗
PubMed1993

Effects of sodium fluoride and cobalt chloride on the enantioselectivity of microsomal and cytosolic esterases in rat intestinal mucosa.

The effects of sodium fluoride (NaF) and cobalt chloride (CoCl2) on the enantioselective hydrolysis of racemic oxazepam 3-acetate (rac-OXA) by microsomal and cytosolic esterases in rat intestinal mucosa were studied. Microsomal and cytosolic esterases hydrolyzed S-OXA and R-OXA in approximately 1:19 and 4:1 ratios, respectively. The hydrolysis of R-OXA by microsomal esterases was inhibited by NaF with an IC50 of 13.4 +/- 1.5 mM. Hydrolyses of both S-OXA and R-OXA by cytosolic esterases were inhibited by NaF with a similar IC50 value (approximately 3 mM). The hydrolysis of S-OXA by cytosolic esterases was inhibited by CoCl2 (IC50 = approximately 5 mM), whereas the hydrolysis of R-OXA by cytosolic esterases was stimulated by approximately 10% in the presence of 1 mM CoCl2. In comparison, the hydrolysis of R-OXA by microsomal esterases was stimulated by approximately 55% in the presence of 1 mM CoCl2. These results not only revealed the effects of NaF and CoCl2 on the catalytic activities of enantioselective cytosolic and microsomal esterases, but also indicated that microsomal and cytosolic esterases that selectively hydrolyzed R-OXA were distinctly different protein entities.

Animals↗
PubMed1993

Dual effect of valproic acid on the pharmacokinetics of phenytoin.

To evaluate the effects of valproic acid on the disposition of phenytoin, a single dose of 600 mg valproic acid and multiple doses of valproic acid (200 mg four times a day for 5 days) were administered together with a single oral dose of 600 mg phenytoin to 12 young male volunteers. Fraction of unbound phenytoin and the area under curve (AUC) of the total and unbound phenytoin in plasma were compared with the control phase in which only 600 mg phenytoin was given. Valproic acid increased the unbound fraction of phenytoin in both single- and multiple-dose studies by 15 per cent and 41 per cent, respectively. Single-dose valproic acid increased the total AUC of phenytoin by 11 per cent. Multiple-dose valproic acid decreased the total AUC by 7 per cent. Single- and multiple-dose valproic acid increased the unbound AUC by 25 per cent and 18 per cent, respectively, probably due to the inhibition on the metabolizing enzymes. We concluded that there are at least two mechanisms involved in valproic acid-phenytoin interaction. Whereas valproic acid displacing phenytoin on the plasma protein decreased the total drug concentration of phenytoin, the enzyme inhibition by valproic acid increased both the total and unbound concentration of phenytoin. The two conflicting mechanisms may result in different effects on the total plasma concentration of phenytoin. Therapeutic drug monitoring based on the total concentration of phenytoin may be misleading when valproic acid is co-administered.

Administration, Oral↗
PubMed1993

Enantioselectivity of esterases in human brain.

Subcellular fractions of three human brain specimens were found to contain esterase activities which hydrolyzed racemic oxazepam 3-acetate (rac-OXA). All three human brain preparations were highly selective toward the S-enantiomer of rac-OXA.

Adult↗
PubMed1993

Molecular basis of genetic variation in debrisoquin hydroxylation in Chinese subjects: polymorphism in RFLP and DNA sequence of CYP2D6.

Debrisoquin hydroxylation phenotype was determined in 124 Chinese persons living in Taiwan, and two poor metabolizers were identified with a urinary metabolic ratio (MR) greater than 12.6. The other subjects, extensive metabolizers, showed a normal frequency distribution of log(MR). Most subjects (50%) showed a 44/29 kb pattern in restriction fragment length polymorphism (RFLP) analysis with use of Xba I, and 30% and 15% of the subjects exhibited a homozygous 29/29 kb and 44/44 kb pattern, respectively. Among extensive metabolizers, subjects with the 44/44 kb pattern had a significant higher log(MR) than those with the 44/29 pattern, and the log(MR) of the subjects with the 44/29 kb pattern was significantly higher than that of the subjects with 29/29 kb pattern. All nine exons and intron 3 of C gamma P2D6 were amplified with polymerase chain reaction (PCR) and sequenced for four extensive metabolizers. Two major polymorphisms were found: one at position 188 of exon 1 and the other at position 4268 in exon 9. With PCR and endonuclease digestion, polymorphisms at exon 1, intron 3, and exon 9 were investigated. Only two of 254 alleles showed a heterozygous guanine at 1934 base pairs (G1934) to adenine (A) mutation, commonly found in white poor metabolizers. Approximately 70% of alleles showed thymine at 188 base pairs (T188), and 76% showed cytosine at 4268 base pairs (C4268) instead of C188 and G4268, as is found in most white subjects. Subjects with T188 or C4268 showed a significant higher log(MR) than subjects with homozygous C188 and G4268. The C/T188, G/A1934, G/C4268, and RFLP polymorphisms may explain the interracial variations between Chinese and white subjects, as well as the genetic variations among Chinese subjects.

Adult↗