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Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 163 records · Page 9Linked to original sources
PubMed1987

Detoxification of styrene oxide by human liver glutathione transferase.

Cytosolic glutathione transferase (GST) was investigated in four human livers. The profile of GST activity was determined by isoelectric focusing using 1-chloro-2,4-dinitrobenzene as the electrophilic substrate. Three livers contained at least one basic and a near-neutral isoenzyme (GST mu). GST mu was not detectable in the fourth liver. The kinetics of GST with styrene oxide as the electrophilic substrate were studied in the cytosolic fraction, with the pooled fractions from isoelectric focusing containing high activity of GST mu transferase, and with GST mu purified to homogeneity. The cytosol obeyed Michaelis-Menten kinetics when styrene oxide was used as the variable substrate. The average (+/- s.e.m.) of the Vmax and Km were 21.9 +/- 7.9 nmol min-1mg-1 and 4.9 +/- 0.4 mM, respectively. At varying concentrations of glutathione, the enzyme did not obey Michaelis-Menten kinetics. Such kinetics were also observed with the fractions from isoelectric focusing and with the homogeneous GST mu fraction. The Eadie-Hofstee plot showed two phases: one with a low and another with a high Km value. The apparent Km values for the cytosol were 0.035 +/- 0.022 and 0.88 +/- 0.36 mM. The kinetic pattern of purified GST mu is consistent with that found in the cytosol.

Adult↗
PubMed1986

Two distinct forms of glutathione transferase from human foetal liver. Purification and comparison with isoenzymes isolated from adult liver and placenta.

Isoelectric focusing of a cytosol fraction from human foetal liver revealed the existence of an acidic and a basic isoenzyme of GSH transferase. The acidic and basic forms of GSH transferase were purified in good yield by use of ion-exchange chromatography on DEAE-cellulose followed by affinity chromatography on S-hexyl-GSH coupled to epoxy-activated Sepharose 6B. The content of the acidic and the basic isoenzymes of GSH transferase together was calculated to constitute 1-2% of the soluble proteins in the hepatic cytoplasm. Physical, catalytic and immunological analyses of the acidic and the basic isoenzymes from foetal liver demonstrated unambiguously that the two forms are different structures with distinct properties. On the other hand, the results show clearly extensive similarities between the foetal acidic transferase and transferase pi from human placenta as well as between the foetal basic form and the basic isoenzymes isolated from adult liver. An exception is that both foetal enzymes seem to be considerably more efficient in catalysing the conjugation of GSH with styrene 7,8-epoxide than the corresponding adult forms of GSH transferase.

Female↗
PubMed1986

Valpromide inhibits human epoxide hydrolase.

The effect of antipileptic drug valpromide (VPM) on the activity of epoxide hydrolase was studied in human adult and foetal liver, kidneys, lungs, intestine and in placenta. The activity of the epoxide hydrolase was measured with both styrene oxide and benzo(a)pyrene-4,5-oxide as substrates. VPM inhibited the epoxide hydrolase obtained from all organs studied. The degree of inhibition was independent of the substrate used. A lowering of the epoxide hydrolase activity by 50% was observed when the concentration of VPM was similar to that of the substrates. VPM competitively inhibited the activity of adult liver epoxide hydrolase with styrene oxide as substrate.

Adult↗
PubMed1986

Metabolism of benzo(a)pyrene in the nuclear and microsomal fractions from rhesus monkey liver.

The metabolism of benzo(a)pyrene was studied in the nuclear and microsomal fractions from four rhesus monkey livers. The nuclear fraction was obtained by differential centrifugation, including a step in 2.3 M sucrose. The metabolites from 3H-benzo(a)pyrene were separated by high performance liquid chromatography (HPLC) and the radioactivity was measured. The nuclear fraction catalyzed the formation of 4,5- and 7,8-dihydrodiols and that of 9-OH and 3-OH phenols. The ratio between the nuclear and microsomal rate of formation of the metabolites ranged between 0.02 and 0.03. The nuclear fraction did not catalyze the formation of 9,10-dihydrodiol or quinones at a detectable rate. In the microsomal fraction there was a preferential formation of 4,5-dihydrodiol and 3-OH phenol. Nuclei differ from the microsomes for the lack of formation of quinones.

Animals↗
PubMed1986

Metabolic interaction between morphine and various benzodiazepines.

The interaction between benzodiazepines and the glucuronidation of morphine was studied in vitro and in vivo. All benzodiazepines tested (diazepam, N-desmethyldiazepam, oxazepam, lorazepam, clonazepam, nitrazepam and flunitrazepam) inhibited the glucuronidation of morphine in vitro in rat liver microsomes. Clonazepam was the most and nitrazepam the least powerful inhibitor, reducing the rate of morphine conjugation by 86% and 42% of the control, respectively, at a substrate and inhibitor concentration of 1.5 mM. Rats given a single oral dose of oxazepam (20 mg per kg body weight) one hour prior to an intraperitoneal dose of morphine (10 mg per kg body weight) had a lower morphine glucuronide/morphine concentration ratio in the 24 hour urine portion than control rats without pretreatment with oxazepam. These data indicate that oxazepam inhibits the glucuronidation of morphine in rats in vivo as well as in vitro.

Animals↗
PubMed1986

Characterization of desmethylimipramine 2-hydroxylation in human foetal and adult liver microsomes.

The rate of formation of 2-hydroxydesmethylimipramine was studied in microsomes from four human foetal and adult livers. The concentrations of desmethylimipramine ranged between 5 and 100 microM. The concentration of 2-hydroxydesmethylimipramine was measured by high pressure liquid chromatography with fluorescence detection. The kinetic parameters (Vmax and Km) were measured by Eadie-Hofstee plot. The Vmax (mean +/- S.E.M.) was 2.80 +/- 0.84 (foetal liver) and 73.1 +/- 11.6 (adult liver) pmol X min.-1 X mg-1. The corresponding values for Km (microM) were 36.3 +/- 6.5 (foetal liver) and 14.1 +/- 1.3 (adult liver). Both parameters were significantly different in foetal and in adult liver. The inhibitory effects of thioridazine, metoprolol, carbamazepine and cimetidine on the 2-hydroxylation of desmethylimipramine were studied in the foetal liver microsomes. Thioridazine and carbamazepine were the most powerful inhibitors.

Adult↗
PubMed1986

Acetyltransferase in humans: development and tissue distribution.

Acetyltransferase with p-aminobenzoic acid (PABA) as substrate was investigated in the cytosolic fraction of the placenta, liver, adrenals, lungs, kidneys, intestine from human fetuses and the liver, lungs, kidneys and intestinal mucosa from adult subjects. All tissue specimens assayed catalyzed the acetylation of PABA at a significant rate. The activity (expressed as nmol of product formed/min/mg protein; mean +/- SE) was 1.10 +/- 0.59 in the fetal liver, 0.66 +/- 0.04 in the placental and 3.87 +/- 0.53 in the adult liver cytosol. Among the fetal tissues, the adrenals had the highest (2.36 +/- 0.78) and the gut the lowest activity (0.71 +/- 0.11). The acetyltransferase activity (mean +/- SE) in the lungs, kidneys and intestinal mucosa from adult subjects was 1.19 +/- 0.15; 1.34 +/- 0.04 and 3.80 +/- 0.34, respectively.

4-Aminobenzoic Acid↗
PubMed1986

Presystemic glucuronidation of morphine in humans and rhesus monkeys: subcellular distribution of the UDP-glucuronyltransferase in the liver and intestine.

Glucuronyltransferase (GT) activity was measured in the homogenate and in the nuclear, mitochondrial and microsomal fractions of liver and intestinal mucosa from man and rats. In man the average rate of morphine glucuronidation was 0.58 and 0.27 nmol/min per mg protein in the homogenates of the liver and intestinal mucosa, respectively. GT was evenly distributed in the different fractions of liver, whereas the major part of the activity in the intestinal mucosa was associated with the nuclear fraction. There was a larger difference between the GT activities in the microsomal fractions of the liver and intestine (0.68 and 0.06 nmol/min per mg, respectively), than between the homogenates of these organs. Similar results were obtained in the rat. GT activity in homogenates of the liver and intestine differed only three-fold whereas there was an 18-fold difference between the microsomal GT activities in these organs.

Animals↗
PubMed1986

Morphine metabolism in mouse brain.

Morphine UDP-glucuronyltransferase activity was demonstrated in the brain of mice from recombinant inbred strains of the BXD series. The formation rate of morphine-3-glucuronide was about 4 fold higher in the progenitor DBA as compared to the C57BL strain.

Animals↗
PubMed1985

Transfer of labetalol into amniotic fluid and breast milk in lactating women.

The transfer of labetalol into human breast milk and amniotic fluid was studied in women with pregnancy hypertension. The women were treated with labetalol 600-1200 mg daily. The ratio between the areas under the milk and plasma concentration versus time curves varied between 0.8 and 2.6. No consistent relation between milk and plasma concentration in the mother was observed either within the individuals during a dose interval or between different individuals. One of the nursed infants at the end of the dose interval had a plasma labetalol in the same range as the mother, and in another infant the level was below the detection limit. Amniotic fluid concentrations 2-3 h after dosing were generally lower than in plasma.

Amniotic Fluid↗
PubMed1985

Prednisolone excretion in human milk.

Six lactating women receiving long-term treatment with prednisolone in doses from 10 to 80 mg/day were studied. Serum and milk samples were assayed for prednisolone and endogenous cortisol by a specific high-performance liquid chromatographic method. The milk and serum concentrations vs time curves for prednisolone were virtually parallel, and the milk concentrations were 5% to 25% of those in serum. The milk/serum concentration ratio increased with increasing serum concentration. At a daily dose of 80 mg prednisolone, the infant would ingest less than 0.1% of that dose; this corresponds to less than 10% of the infant's endogenous cortisol production. Because there is an equilibrium between the concentration of prednisolone in milk and serum, the exposure of the infant is minimized if breast-feeding is avoided during the first 4 hours after the dose. We conclude that from a quantitative point of view the exposure of the infant is minimal, and breast-feeding may be permitted at maternal prednisolone doses of at least 20 mg once or twice daily. At higher doses, exposure may be minimized if nursing is performed greater than 4 hours after the dose.

Female↗
PubMed1985

Pregnancy-induced increase in metoprolol metabolism.

Five women who developed hypertension during pregnancy received metoprolol, 10 mg iv; 3 days later they received metoprolol, 100 mg by mouth. Blood and urine samples were collected after each dose. The same procedure was repeated 3 to 6 months after delivery. The apparent oral clearance of metoprolol during pregnancy exceeded that after pregnancy by a factor of 2 to 13. As a result, after oral dosing the peak plasma concentrations during pregnancy were only 12% to 55% those after delivery, and the plasma AUCs were reduced to the same extent. Oral bioavailability increased by a factor of 1.3 to 3.7 after pregnancy. Systemic clearance after pregnancy was 26% to 97% that during pregnancy, but this difference was not significant. Metoprolol plasma protein binding was the same on both study occasions. Our data cannot be explained by a change in gastrointestinal absorption, because the urinary recovery of metoprolol and its metabolites was slightly higher during pregnancy. It is concluded that the greater metoprolol clearance during pregnancy results from increased hepatic metabolism of the drug.

Adult↗
PubMed1985

Ultrafiltration compared with equilibrium dialysis in the determination of unbound phenytoin in plasma.

Protein binding of phenytoin (PHT) was studied in 36 patients with normal kidney function and six uremic patients. We compared a newly introduced ultrafiltration (UF) technique (EMIT Free Level System I) for measuring unbound PHT in plasma with an equilibrium dialysis (ED) method. The precision of the UF method was satisfactory (the CV within samples was 4.2%, and between days, 3.4%). PHT concentrations were measured with both homogeneous enzyme immunoassay and high performance liquid chromatography using plasma samples from epileptic patients. The values obtained agreed well. Unbound concentrations of PHT determined by the UF technique and ED were identical in both normal and uremic plasma obtained from patients under treatment. Unbound concentrations of PHT correlated significantly to total concentrations in both groups of patients. The investigated UF technique thus appears to be accurate for measuring unbound concentrations of PHT in plasma. Controlled clinical studies are required to show that this is a cost-effective clinical service.

Blood Proteins↗
PubMed1985

Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation.

The kinetics of morphine and formation of the main metabolite, morphine-3-glucuronide (M3G) after single and intravenous doses of morphine were studied in six cancer patients and compared with the formation rate of M3G in vitro in microsomes isolated from liver biopsies obtained from the same patients at palliative laparotomy. The results showed that high formation rates of M3G in vitro in microsomes isolated from liver biopsies were associated both with high apparent oral clearance values and high M3G/morphine AUC (area under the concentration vs time curve) ratios as measured in vivo in the same patients. In accordance with previous results marked interindividual differences were seen in the kinetics of morphine; the oral bioavailability varied between 30 and 69% and the systemic plasma clearance between 18.6 and 34.0 ml min-1 kg-1. This variation correlated with the variation in morphine metabolism as assessed in vitro. In vivo, a high M3G/morphine AUC ratio predicted a high oral clearance. Hepatic UDP-glucuronyl transferase activity is thus an important determinant of the in vivo kinetics of orally administered morphine.

Administration, Oral↗