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Biomedical subjects

A Rane

Publications and source records attributed to A Rane.

At least 145 records · Page 8Linked to original sources
PubMed1989

Development of the glucuronyltransferase and sulphotransferase towards 2-naphthol in human fetus.

The activity of the microsomal glucuronyltransferase (GT) was measured in 34 fetal and 27 adult human livers with 2-naphthol as substrate. The average (+/- SD) enzyme activity was 0.07 +/- 0.07 nmol/min/mg protein (fetal) and 7.98 +/- 4.19 nmol/min/mg protein (adult) livers. The adult to fetal ratio of the GT activity was 114. The activity of the cytosolic sulphotransferase (ST) was measured with 2-naphthol as substrate in 30 fetal and 23 adult livers. ST activity (mean +/- SD) was 0.18 +/- 0.12 nmol/min/mg protein (fetal) and 0.63 +/- 0.22 nmol/min/mg protein (adult). The adult to fetal ratio of the ST activity was 3.5. The postnatal development of GT is more marked than that of ST. In the fetal livers, the rate of 2-naphthol sulfation correlated (p less than 0.01) with the rate of 2-naphthol glucuronidation, whereas they did not correlate in the adult livers. No relationship was observed between the activity of the GT or ST and gestational age. The correlation existing between ST and GT in human fetus might suggest that the two enzymes are under a common developmental pattern which seems to be independent of gestational age. The activity of the GT with morphine as substrate was measured in 25 fetal and 29 adult livers and found to be 0.23 +/- 0.20 nmol/min/mg protein (fetal) and 1.85 +/- 0.98 nmol/min/mg protein (adult). Thus, the adult to fetal ratio of morphine glucuronidation was 8.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Perinatal opiate exposure. Effects on metabolism of xenobiotics and steroids in adult rat liver.

The effects of perinatal or neonatal morphine exposure on the hepatic steroid and xenobiotic metabolism in adult rats were studied. Early morphine exposure did not affect the 16 alpha-hydroxylation or 5 alpha-reduction of androstenedione in either sex, but decreased the 7 alpha- and 6 beta-hydroxylations in both sexes. Morphine exerted a suppressive effect on the ethoxyresorufin-O-deethylase activity and increased the ethoxycoumarin-O-deethylase activity in both sexes. Morphine exposure did not significantly affect its own N-demethylation or the total cytochrome P-450 content in the liver. Neonatal morphine exposure caused a significant decrease in body and testes weight in the adult male rat. We conclude that the effects of morphine are not confined to sex-differentiated pathways and are similar in both sexes.

Animals↗
PubMed1989

Positron emission tomography in studies on fetomaternal disposition of opioids.

The noninvasive radiotracer technique, positron emission tomography, has been applied in studies on the transfer of drugs from mother to fetus in Rhesus monkeys. 11C-labelled morphine or heroin was administered intravenously to pregnant monkey and the radioactivities with time were measured in the placenta, fetal liver and maternal blood. The information from the 11C-morphine experiment was supplemented with data from the simultaneous administration of 14C-morphine followed by the analysis of unchanged drug and metabolites in maternal blood and also in one sample from fetal blood. In placenta, 11C-morphine and 11C-heroin rapidly reached high radioactivities already within the first few minutes after administration. The transfer of 11C-morphine-derived radioactivity to the fetus was also rapid, although there was a lag-time in relation to the placental uptake. The elimination rate of the radioactivity was fast from the blood, placenta and the fetal liver and in plasma there was a rapid appearance of conjugated morphine metabolites. The fetal plasma concentration of morphine was twice that in maternal plasma 100 min after injection. The transfer of 11C-heroin-derived radioactivity to the fetus was even faster than was the elimination of radioactivity. The plasma kinetics of morphine in the mother and fetus was simulated in a compartment flow model and simulated concentrations agreed well with measured values.

Animals↗
PubMed1988

Monoclonal antibody directed detection of cytochrome P-450 (PCN) in human fetal liver.

Monoclonal antibodies (MAbs) raised to rat liver cytochrome P-450s induced by phenobarbital, 3-methylcholanthrene, and pregnenolone-16 alpha-carbonitrile were used to detect these epitope specific P-450s in human abortion fetuses 14-24 weeks of age. This was performed using a Western blot technique. In parallel, ECOD was determined in the same tissue specimens. Of seven different MAbs used MAb PCN 2-13-1/C2 was the only one that immunodetected a cytochrome P-450 band with Western blot analyses of human fetal liver microsomes. This band was consistently detected in all fetal liver specimens studied although the intensity varied among samples. No bands were detected in microsomal preparations from adrenal and renal tissues obtained from the same fetuses. The human adult liver microsomal specimens also contained a MAb PCN 2-13-1/C2 identified cytochrome P-450 band. ECOD activity was detected in all but one of the human fetal livers and varied between 0.22 and 47.5 pmol min-1 mg protein-1, as compared to 113 to 489 pmol min-1 mg protein-1 in human adult livers. In all of the fetuses except one the adrenal ECOD activity (0.63-37.0 pmol min-1 mg protein-1) exceeded that in the liver. The renal ECOD activities were, however, low. The hepatic and adrenal ECOD activities correlated with each other (r = 0.95). Although the ECOD activity is a function of several different P-450s there was also a correlation (r = 0.78) between the ECOD activity and the MAb immunodetected protein band intensity in Western blots of human fetal liver microsomes. The presence of a MAb PCN 2-13-1/C2 identified band in fetal liver microsomes may be indicative of a steroid-dependent effect in fetal life.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Profile of drug metabolizing enzymes in the nuclear and microsomal fractions from rat liver nodules and normal liver.

The activities of UDP-glucuronyl transferase, DT-diaphorase, epoxide hydrolase, aryl hydrocarbon hydroxylase, gamma-glutamyl transferase and NADPH-cytochrome c reductase were measured in the nuclear and microsomal fractions from normal rat liver and rat liver nodules. Nodules were produced by intermittent feeding of Wistar rats with a standard diet supplemented with 0.05% (w/w) 2-acetylaminofluorene. The nuclear and microsomal fractions were isolated by differential centrifugation. The activities of UDP-glucuronyl transferase, DT-diaphorase, epoxide hydrolase and gamma-glutamyl transferase were significantly increased in the nuclear and microsomal fractions obtained from nodules as compared with normal liver. Aryl hydrocarbon hydroxylase activity was decreased in the microsomal fraction from the pathological tissue but not in the nuclear fraction. NADPH-cytochrome c reductase activity was similar in nodular and normal liver tissue. The nuclear/microsomal ratio for phase I reactions in xenobiotic metabolism was increased over normal more than two fold. Thus the nuclear and microsomal systems for drug metabolism are both changed in liver nodules. The relative enhancement of nuclear activating reactions is remarkable in the light of the increased risk for malignant transformation exhibited by nodular cells.

2-Acetylaminofluorene↗
PubMed1988

Cytosolic epoxide hydrolase in humans: development and tissue distribution.

Cytosolic epoxide hydrolase activity was measured towards trans-stilbene oxide in 41 human adult livers, in 40 fetal livers, in 17 placentas and in fetal and adult lungs, kidneys and gut. The cytosolic epoxide hydrolase activity was measurable in all specimens investigated. The rate of formation of trans-stilbene glycol (pmol/min per mg protein, mean +/- SD) was 55.2 +/- 89.6 (fetal liver). 303.2 +/- 73.2 (adult liver) and 18.8 +/- 13.1 (placenta) In the fetal extrahepatic tissues, the cytosolic epoxide hydrolase activity was 70.0 +/- 9.4 (adrenals), 47.6 +/- 7.2 (gut), 69.4 +/- 22.5 (kidneys) and 43.2 +/- 19.2 (lungs) pmol/min per mg protein, whereas in the adult tissues it was 131.2 +/- 63.1 (kidneys), 27.8 +/- 20.3 (intestine), 8.5 +/- 2.8 (lungs) and 7.2 +/- 4.2 (urinary bladder) pmol/min per mg protein.

Adult↗
PubMed1988

Glutathione S-transferase in humans: development and tissue distribution.

Glutathione S-transferase (GST) was investigated with benzo(a)pyrene-4,5-oxide (BPO) as substrate in tissue specimens from 26 fetal and 27 adult livers and 27 placentas. The average (+/- SEM) of GST activity in the cytosol was 1.80 +/- 0.18 (fetal liver), 3.05 +/- 0.30 (adult liver) and 1.18 +/- 0.07 (placenta) nmol/min/mg. GST was also investigated in human fetal and adult lungs, kidneys and gut. In these tissues the average (+/- SEM) GST activity ranged between 0.71 +/- 0.12 (adult intestine) and 2.11 +/- 0.18 (fetal lungs) nmol/min/mg. Whereas in the fetal liver the conjugation of BPO was catalyzed at a rate of about two-thirds of the adult rate, similar or higher GST activities were found in the fetal non-hepatic tissues as compared to the adult organs. No correlation was found between the activity of the GST in fetal liver and placenta and the gestational age (11-25 weeks). GST develops before the 11th week of gestation and it does not undergo changes during the mid-gestation. No correlation was found between GST activity in adult liver and age (32-70 years).

Adult↗
PubMed1988

Presence of epoxide hydrolase and glutathione S-transferase in human pulmonary alveolar macrophages.

Pulmonary alveolar macrophages (PAMs) were obtained from 11 patients by bronchoalveolar lavage. Epoxide hydrolase and glutathione S-transferase in sonicated PAMs were measured using benzo(a)pyrene-4,5-oxide as the substrate. The activity of epoxide hydrolase was 0.24 +/- 0.10 nmol/min/mg protein (mean +/- SD), and of glutathione S-transferase 0.22 +/- 0.12 nmol/min/mg protein. There was a significant difference in enzyme activities in the PAMs from smokers and non-smokers. Epoxides may be metabolized in PAMs.

Epoxide Hydrolases↗
PubMed1988

Excretion of tiapamil in breast milk.

The excretion of tiapamil in breast milk was studied in six lactating mothers (3-7 days post partum) following a single oral 600 mg dose of the drug. The milk/plasma ratio of tiapamil derived from the areas under the plasma and milk concentration-time curves was 0.44 +/- 0.10 mean +/- s.d.). Assuming an intake of 350 ml of milk during a dosing interval of 12 h, the newborn would be exposed at the maximum to 0.053 mg tiapamil. This small amount does not represent a risk for the baby.

Adult↗
PubMed1988

Human liver morphine UDP-glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam.

1. Morphine uridine diphosphate glucuronyl transferase (UDP-GT) was studied in human liver microsomes. The (-)- and (+)-morphine enantiomers were used as substrates and inhibitors, such as oxazepam and various opioid congeners were employed to characterize the different glucuronidation pathways. The kinetics of the oxazepam inhibition were studied in the rat liver. 2. The overall glucuronidation of (+)-morphine was higher than that of (-)-morphine. The morphine congeners tested, potently inhibited the formation of (-)-morphine-3-glucuronide ((-)-M3G), except for normorphine and codeine. The formation of (+)-morphine-6-glucuronide [+)-M6G) was potently inhibited by only dextromethorphan and (+)-naloxone. All drugs except normorphine inhibited the formation of (+)-M3G by 18-50%. 3. The metabolism of (-)-morphine to (-)-M3G was more sensitive to oxazepam inhibition than the formation of (+)-M3G from (+)-morphine in the rat liver. 4. The glucuronidation of natural morphine is subject to in vitro interaction with oxazepam and several opiate drugs. Our study supports the theory of more than one type of UDP-GT being involved in morphine glucuronidation.

Animals↗
PubMed1988

7-Ethoxycoumarin and 7-ethoxyresorufin O-deethylase in human foetal and adult liver: studies with monoclonal antibodies.

The 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylase activities were investigated in the microsomal fractions from 5 human adult and 3 foetal livers and 5 human foetal adrenals. The enzyme activity expressed as pmol/min. per mg microsomal protein was higher with 7-ethoxyresorufin as substrate in all investigated specimens with average values (+/- S.E.M.) of 74 +/- 27, 13 +/- 3 and 12 +/- 1 in adult and foetal livers and foetal adrenals, respectively. Monoclonal antibodies raised against 3-methylchloranthrene or phenobarbital induced rat liver cytochrome P-450 were investigated with respect to their inhibiting effects on the rate of O-deethylation of both substrates in human adult liver. Only the monoclonal antibody against the 3-methylcholanthrene induced cytochrome P-450 inhibited the O-deethylation of 7-ethoxyresorufin to 64 to 79 percent of control values. The other antibody had no effect on this or the other O-deethylase activity. Thus, the 7-ethoxyresorufin O-deethylase is partly catalyzed in human adult liver by a cytochrome with an epitope that is recognized by the monoclonal antibody against 3-methylcholanthrene induced rat liver cytochrome P-450. With foetal liver the low activity of the enzyme became unmeasurable in the presence of this antibody.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Ontogenic development of 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylase in the rat and effect of monoclonal antibodies.

The O-deethylase activities with 7-ethoxycoumarin (ECDE) and 7-ethoxyresorufin (ERDE) as substrates were investigated in the liver microsomal fraction of newborn, 1 week, 2 weeks, 1 month and 2 months old rats. The rates of O-deethylation of both substrates were lowest in newborn rats at which stage the specific activities (pmol x min.-1 x mg-1 protein; mean +/- S.D.) of ECDE and ERDE were 19.0 +/- 0.2 and 6.0 +/- 0.5, respectively. In 1 week old animals, the rate of ECDE had reached the highest values (270 +/- 81 pmol x min.-1 x mg-1 protein). Thereafter, it decreased to a minimum (70.9 +/- 14.8 pmolmin.-1 x mg-1 protein) at 2 months of age. The rate of ERDE reached the highest activity (129 +/- 7.1 pmol x min.-1 x mg-1 protein) in 1 month old animals. The effects monoclonal of antibodies (MAb), on ECDE and ERDE were studied. The MAb were raised against 3-methylcholanthrene (MAb 1-7-1) or phenobarbital (MAB 2-66-3) induced rat liver microsomal cytochrome P-450. Only the former antibodies were inhibitory to the O-deethylation of 7-ethoxyresorufin. This reaction was inhibited to a similar extent (by 31-33%) in rat liver microsomes from 1 week and 2 months old animals. None of the antibodies exerted any effect on the O-deethylation of 7-ethoxycoumarin.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1988

Sulfotransferase in humans: development and tissue distribution.

Sulfotransferase with 2-naphthol as substrate was investigated in the cytosolic fraction of human fetal liver, lungs, kidneys, adrenal glands, intestine and placenta and also in liver, lungs, kidneys, intestinal and urinary bladder mucosa from human adult subjects. All tissue specimens assayed catalyzed the sulfation of 2-naphthol at a significant rate. The activity (expressed as pmole per minute per milligram protein; mean +/- SD) was 211 +/- 197 (n = 46) fetal liver; 22 +/- 12 (n = 29) placenta; 625 +/- 205 (n = 42) human adult liver. In fetal kidneys (576 +/- 177; n = 6) and gut (558 +/- 293; n = 6) the activity was twice as high as in liver. In the lungs (273 +/- 125; n = 6) and in the adrenals (174 +/- 119; n = 19) the sulfotransferase activity was comparable with the hepatic one. In human adult extrahepatic tissues the highest activity was found in the intestinal mucosa (153 +/- 49; n = 4) and the lowest one in the urinary bladder mucosa (16 +/- 4; n = 4). This paper shows that the sulfotransferase has a wide distribution in the human fetus and the distribution pattern of this enzyme is different in the human fetus and adult subject.

Adult↗
PubMed1988

Conjugation of styrene oxide by the basic and acidic forms of glutathione transferase in the human fetal liver.

Two forms of glutathione transferase were isolated by means of isoelectric focusing of human fetal liver cytosol preparations. The enzyme activity was measured with 1-chloro-2,4-dinitrobenzene as the electrophilic substrate. One peak focused at pH 9-10 (basic form) and the other at pH 4-5 (acidic form). The basic and the acidic forms are representatives of glutathione transferase classes alpha and tau, respectively. These classes constitute two of the three classes defined for cytosolic forms of the enzyme in several mammalian species [Mannervik et al., Proc. natn. Acad. Sci. USA 82: 7202-7206, 1985]. Only the basic fraction isolated from human fetal liver catalyzed the conjugation of styrene oxide with glutathione at a significant rate. The kinetics of this form were studied keeping the concentration of styrene oxide constant (6 mM) and varying the glutathione concentration from 0.05 to 25 mM. The enzyme activity displayed non-Michaelis-Menten kinetics. The basic and acidic forms of glutathione transferase from a fetal liver were purified to homogeneity. Both purified forms catalyzed the conjugation of glutathione with styrene oxide. The kinetics were studied at varying glutathione concentrations and for both forms, it was found to be of a non-Michaelis-Menten type. The results are consistent with previous findings in the cytosolic fraction [Pacifici et al., Biochem. Pharmac. 30: 3367-3371, 1981] and show that the non-Michaelian kinetics observed with glutathione in human fetal liver cytosol are reflections of the intrinsic properties of the basic as well as the acid form of this enzyme and not primarily depending on the simultaneous catalytic action of the two forms.

Cytosol↗
PubMed1987

Plasma protein binding of clonazepam in hepatic and renal insufficiency and after hemodialysis.

The plasma protein binding of clonazepam was investigated in healthy volunteers, cirrhotic patients, chronic uremic patients maintained on hemodialysis, and patients with reduced renal function. Each group consisted of six subjects. The unbound fraction of clonazepam (mean +/- SEM) was 13.9 +/- 0.2% in volunteers. 17.1 +/- 1.0% in cirrhotic patients, 1.56 +/- 0.5% before and 12.2 +/- 0.4% after hemodialysis in chronic uremic patients, and 16.0 +/- 0.7% in patients with poor renal function. The figure for the healthy subjects was significantly different from that of cirrhotic patients only. Binding of clonazepam to albumin and alpha 1-acid glycoprotein was also studied. Clonazepam bound preferentially to albumin.

Adult↗
PubMed1987

Apparently normal phenytoin metabolism in a patient with phenytoin-induced rash and lymphadenopathy.

A 10-year old female on phenytoin therapy developed a rash and lymphadenopathy. H.p.l.c. assays of urinary metabolites indicated no differences in stereoselective metabolism of phenytoin to phenolic and dihydrodiol metabolites as compared with volunteers given the drug or with pediatric patients without adverse reactions. This suggests that no obvious difference in stereoselective metabolism of phenytoin to potentially toxic arene oxides exists between this patient and other patients on phenytoin. Our results are consistent with the hypothesis that differences in peripheral detoxication of phenytoin arene oxides and not differences in hepatic metabolism of phenytoin may be responsible for such adverse reactions.

Child↗
PubMed1987

Systemic concentrations of metronidazole and its main metabolites after intravenous oral and vaginal administration.

Metronidazole kinetics was studied in 5 healthy women after a single dose given intravenously, orally or vaginally, 500, 400 and 500 mg, respectively. Serum levels of the drug and of its hydroxy and acid metabolites were assessed. The results after intravenous and oral boluses were consistent with previous reports. After vaginal dose maximum serum levels of about 1 microgram/ml of the drug were obtained between 9 and 24 h after the dose. Maximum concentration of the hydroxy metabolite was about 0.3 microgram/ml after 24 h. Bioavailability of the drug was 19 +/- 3% after the vaginal dose as compared to 100 +/- 5% after the oral dose. Daily insertion into the vagina of 500 mg metronidazole resulted in a maximum serum concentration of 1.2 +/- 0.2 microgram/ml of the parent drug and of 0.6 +/- 0.1 microgram/ml of the hydroxy metabolite after about 3 days (range 2-4) after which no accumulation was noted. Urinary excretion of the metabolites was considerably lower after vaginal than after intravenous or oral administration, but the proportion between the two metabolites in the urine was constant.

Administration, Intravaginal↗