Effect of lithium on hepatic drug-metabolizing enzymes of protein-deficient rats

Protein deficiency was produced by feeding synthetic 8%-protein diet. Lithium carbonate at the dose level of 1.1g/kg diet was administered to normal and protein-deficient rats for a period of one mo. A significant inhibition in the levels of cytochrome (cyt) P450, cyt b5, glutathione (GSH), glutathione S-transferase (GST) and glutathione peroxidase (GPx), but an increase in gamma-glutamyl transpeptidase (gamma-GT), was observed in low-protein LP-fed rats. Lithium treatment to normal rats caused no significant change in the activities of cyt P450, cyt b5, GST, and GSH levels, whereas there was elevation in the activities of gamma-GT and GPx and suppression in glutathione reductase (GRd) activity. Lithium administration to LP-fed rats resulted in significant increases in the hepatic gamma-GT and GPx activities.     

Effects of aspirin on arylamine N-acetyltransferase activity in Klebsiella pneumoniae

This study was designed to assess the effects of aspirin on arylamine N-acetyltransferase (NAT) activities in the bacterium Klebsiella pneumoniae using high performance liquid chromatography to measure the acetylation of 2-aminofluorene (2-AF) with or without aspirin. Cytosols or suspensions of K. pneumoniae with or without specific concentrations of aspirin co-treatment showed different percentages of 2-AF acetylation. The data indicated that there was decreased NAT activity associated with increased levels of aspirin in K. pneumoniae cytosols and in intact bacteria. For the cytosol examination, the apparent values of Km and Vmax decreased 0.59- and 0.58-fold after co-treated with 40 microM aspirin, respectively, for 2-AF. For the intact bacteria examination, the apparent values of Km and Vmax decreased 0.60- and 0.67-fold after co-treated with 40 microM aspirin, respectively, for 2-AF. This report is the first demonstration to show that aspirin can decrease N-acetyltransferase activity in the bacterium K. pneumoniae.     

Changes in drug-metabolizing enzymes of rats in ciprofibrate-induced hepatic nodules

1. Premalignant rat liver nodules produced in the resistant hepatocyte model, by exposure to carcinogenic chemicals (diethyl nitrosamine and 2-acetamidofluorene), and partial hepatectomy, exhibit decreased xenobiotic hydroxylase activities and increased conjugase activities, which are considered responsible for increased resistance to xenobiotic toxicity. 2. However, premalignant rat liver nodules generated by feeding the hypolipidaemic, peroxisomal proliferating drug, ciprofibrate, in a hypolipidaemic model, exhibit decreased hydroxylase activities but decreased conjugase activities also. 3. It is considered that reactive oxygen species (ROS) are generated in both the resistant hepatocyte model and in the hypolipidaemic model, resulting in lipid peroxidation, loss of haem, cytochromes and hydroxylase activities. 4. However, whereas there is a rebounding compensation of conjugase enzymes in the resistant hepatocyte model, this does not occur with the hypolipidaemic model, as peroxidation is probably persistent and the conjugases are continuously destroyed.     

Effects of erythromycin on hepatic drug-metabolizing enzymes in humans

In rats, erythromycin has been shown to induce microsomal enzymes and to promote its own transformation into a metabolite which forms an inactive complex with reduced cytochrome P-450. To determine whether similar effects also occur in humans, we studied hepatic microsomal enzymes from six untreated patients and six patients treated with erythromycin propionate, 2 g per os daily for 7 days. In the treated patients, NADPH-cytochrome c reductase activity was increased; the total cytochrome P-450 concn was also increased but part of the total cytochrome P-450 was complexed by an erythromycin metabolite. The concn of uncomplexed (active) cytochrome P-450 was not significantly modified and the activity of hexobarbital hydroxylase remained unchanged. We also measured the clearance of antipyrine in six other patients; this clearance was not significantly decreased when measured again on the seventh day of the erythromycin propionate treatment. We conclude that the administration of erythromycin propionate induces microsomal enzymes and results in the formation of an inactive cytochrome P-450-metabolite complex in humans. However, the concn of uncomplexed (active) cytochrome P-450 and tests for in vitro and in vivo drug metabolism were not significantly modified.     

Anticonvulsant activity of enzyme inhibitors in rats

Three liver microsomal enzyme inhibitors, proadifen, 2,4-dichloro-6-phenylphenoxyethyldiethylamine, and 2,4-dichloro-6-phenylphenoxyethylamine, and a hepatotoxic agent, carbon tetrachloride, were tested for anticonvulsant activity in adult male albino rats using the maximal electroshock seizure technique. All four substances exhibited significant anticonvulsant activity 1 hr after intraperitoneal administration. This protection was absent when tested 24 hr later.     

Effect of endurance training on pancreatic enzyme activity in rats

Immunoglobulin G (IgG) of Indian soft-furred rat, Millardia meltada, was purified by an immunoaffinity chromatography and antibodies against it was raised in rabbit. Using this rabbit anti-M. meltada IgG antibody, sensitivity of enzyme-linked immunosorbent assay (ELISA) to measure parasite-specific antibodies in the sera of M. meltada was markedly enhanced than the previous method using rabbit anti-mouse IgG and rabbit anti-rat IgG antibodies, which could cross-react to M. meltada IgG. Since M. meltada could effectively produce circulating antibodies against two intestinal helminths, Strongyloides venezuelensis and Nippostrongylus brasiliensis, the high susceptibility of this animal to an array of parasites seems to be not due to general immunological deficiency.     

Time-dependent effects of antidepressant drugs on the low dose of apomorphine-induced locomotor hypoactivity in rats

Surfactant deficiency in newborn infants with hyaline membrane disease (HMD) reduces peripheral airway stability, leading to lung atelectasis, inhomogeneity of distribution of ventilation, ventilation/perfusion mismatch, and hypoxemia. The aim of this study was to evaluate the immediate effect of exogenous surfactant treatment on ventilation inhomogeneity (VIH) in infants with HMD. Homogeneity of ventilation was measured repeatedly in ten infants (median gestational age 30 weeks and birthweight 1.50 kg) after Exosurf, and in six infants (median gestational age 30 weeks and birthweight 1.42 kg) after Survanta treatment. Lung function was measured before and 0.5, 2, and 6 hours after administration of a single dose of surfactant. The multiple breath nitrogen washout method was used to measure the time pattern of nitrogen elimination from the lungs. VIH was evaluated by using both a compartmental lung model and a model-independent moment analysis. The two-compartment lung model was found to dominate before surfactant treatment, while a single-compartment model (implying homogeneous ventilation) fitted the washout data best 6 hours after Exosurf treatment (P < 0.01). The same pattern occurred 2 hours after Survanta administration. Moment analysis confirmed the reduction in VIH by both surfactants. This study supports the hypothesis that the improved oxygenation after surfactant treatment in infants with HMD results from a reduction in VIH and an increase in functional residual capacity (FRC).     

Salicylate-enhanced exposure of Klebsiella pneumoniae subcapsular components

Viable and non-viable cells in coronary and internal thoracic arteries, collected at autopsy 7-24 h post-mortem from individuals 15-81 years of age, were detected using the fixable fluoroprobes 5-chloromethylfluorescein diacetate (green) and ethidium homodimer-1 (orange/red). Viability status of individual endothelial and smooth muscle cells was confirmed by simultaneous autoradiographic detection of incorporated [3H]glucosamine. Twenty-five percent of coronary and 42% of internal thoracic arteries contained viable cells up to 24 h following death. For the majority of viable vessels the mean percentage of viable cells ranged between 60 and 80% with no significant difference between coronary and internal thoracic arteries and no relationship with either age of the donor or with time to autopsy. Non-viable cells were usually distributed fairly evenly amongst viable cells but this pattern could not be assumed. In a number of vessels non-viable cells were variably clustered in different regions of vessel wall. These findings confirm that vessels sampled at autopsy can be used for metabolic studies with the caveat that assessment of cell viability is a necessary prerequisite for interpretation of results.     

Effects of antipsoriatic therapies on hepatic microsomal enzyme activity in patients with psoriasis

OBJECTIVE: The influence of several antipsoriatic therapies on microsomal enzyme activity was assessed by comparing measurements of antipyrine kinetics prior to and two weeks after initiation of therapy. METHODS: Serum and urine analysis was carried out by means of high performance liquid chromatography (HPLC). Each form of therapy was examined separately. 10 patients were treated with etretinate. The groups treated with 8-methoxypsoralene (8-MOP) in combination with UVA irradiation (PUVA), etretinate in combination with PUVA (RePUVA), anthralin, or combined UVA and UVB irradiation (SUP) consisted of 7 patients each. RESULTS: Neither anthralin nor SUP therapy led to any significant changes in antipyrine kinetics. Antipyrine clearance under the other regimens was, however, reduced. It was 23% lower in PUVA-treated patients, 20% lower in those receiving retinoids and 28% lower in those under RePUVA (p<0.05 - 0. 01). CONCLUSIONS: PUVA, etretinate and RePUVA inhibit microsomal enzyme activity in the liver. Possible drug interactions with other P subset450 inducing or inhibiting agents should be considered in the therapy of psoriatic patients.     

The effects of duodenal glucose infusion on some hepatic enzyme activities in sheep

1. Two experiments were performed to examine the effects of duodenal glucose infusion on hepatic enzyme activities in sheep. 2. Glucose infusion significantly increased the specific activities of phosphofructokinase, pyruvate kinase and 6-phosphogluconate dehydrogenase and significantly reduced the specific activity of glucose-6-phosphatase suggesting that the pathways of glucose breakdown are increased, and gluconeogenesis decreased, in glucose-infused animals. 3. The results are discussed in relation to the effects of diet on liver metabolism in sheep.     

Energy-dependent accumulation of fluoroquinolones in quinolone-resistant Klebsiella pneumoniae strains

The intracellular accumulation of norfloxacin and pefloxacin in Klebsiella pneumoniae was evaluated. The roles of lipopolysaccharide, capsule, and outer membrane proteins were not important for the intrabacterial accumulation of fluoroquinolones in isogenic strains with known outer membrane alterations. In fluoroquinolone-resistant clinical isolates also expressing GyrA alterations, an active efflux leading to decreased accumulation of the drugs enhanced their resistance to these agents.     

Plasmid profiles of Klebsiella pneumoniae isolated from horses

Plasmid profiles of Klebsiella pneumoniae isolated from horses were examined. Thirty-nine strains of K. pneumoniae capsular type 1 (K1) isolated from cervical swabs of mares suffering from metritis, and from semen of stallions showed similar plasmid profile patterns, and all strains possessed a 125 megadaltons (Md) plasmid. There was no difference in plasmid profiles between the heavily-encapsulated and the less heavily-encapsulated strains of K. pneumoniae K1. Non-capsulated variants derived from the strains of K1 showed the same plasmid profile pattern as the parent strains. Plasmid profiles of K. pneumoniae other than K1 were various, and none of these strains possessed the 125 Md plasmid.     

Nonlinear protein binding and enzyme heterogeneity: effects on hepatic drug removal

The kinetics of substrate removal by the liver and the resulting nonlinear changes in unbound fraction along the flow path at varying input drug concentrations were examined by a model simulation study. Specifically, we varied the binding association constant, KA, and the Michaelis-Menten constants (Km and Vmax) to examine the steady state drug removal (expressed as hepatic extraction ratio E) and changes in drug binding for (i) unienzyme systems and (ii) simple, parallel metabolic pathways; zonal metabolic heterogeneity was also added as a variable. At low KA, E declined with increasing input drug concentration, due primarily to saturation of enzymes; only small differences in binding were present across the liver. At high KA, a parabolic profile for E with concentration was observed; changes in unbound fraction between the inlet and the outlet of the liver followed in parallel fashion. Protein binding was the rate-determining step at low input drug concentrations, whereas enzyme saturation was the rate-controlling factor at high input drug concentration. Heterogeneous enzymic distribution modulated changes in unbound fraction within the liver and at the outlet. Despite marked changes in unbound fraction occurring within the liver for different enzymic distributions, the overall transhepatic differences were relatively small. We then investigated the logarithmic average unbound concentration and the length averaged concentration as estimates of substrate concentration in liver in the presence of nonlinear drug binding. Fitting of simulated data, with and without assigned random error (10%), to the Michaelis-Menten equation was performed; fitting was repeated for simulated data obtained with presence of a specific inhibitor of the high-affinity, anteriorly distributed pathway. Results were similar for both concentration terms: accurate estimates were obtained for anterior, high affinity pathways; an overestimation of parameters was observed for the lower affinity posteriorly distributed pathways. Improved estimations were found for posteriorly distributed pathways upon inhibition with specific inhibitors; with added random error, however, the improvement was much decreased. We applied the method for fitting of several sets of metabolic data obtained from rat liver perfusion studies performed with salicylamide (SAM) (i) without and (ii) with the presence of 2,6-dichloro-4-nitrophenol (DCNP), a SAM sulfation inhibitor. The fitted results showed that SAM sulfation was a high-affinity high-capacity pathway; SAM glucuronidation was of lower affinity but comparable capacity as the sulfation pathway, whereas SAM hydroxylation was of lower affinity and lower capacity.