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PubMed1983

Drug metabolism activities of isolated rat hepatocytes in monolayer culture.

The levels of cytochrome P-450 in hepatocytes cultured as monolayers for 22 hrs in Dulbecco's modified Eagle medium supplemented with serum and insulin was reduced to approximately 40% of initial values of freshly isolated hepatocytes. In correspondence with this the activities of the cytochrome P-450 monooxygenases aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) and ethylmorphine (EM) N-demethylase were reduced to 40 and 22% of their initial activities, respectively. Modifying the culture medium through omission of cysteine and cystine, and adding dexamethazone and delta-amino levulinic acid, increased the content of cytochrome P-450 to 59% and EM N-demethylase to 46% of initial values, but was without effect on AHH activity. However, further modifications by adding high concentrations of asparagine and leucine increased AHH activity to 62% of initial values, but did not further enhance the total content of cytochrome P-450 or the EM N-demethylase activity. The activities of cytochrome P-450 reductase, flavin containing monooxygenase, epoxide hydrolase and glutathione S-transferase decreased less (to about 70-80% of initial values) than cytochrome P-450 associated monooxygenase activities, whereas UDP-glucuronyl transferase decreased to about 50% of initial values. In contrast to what was observed regarding cytochrome P-450 and associated monooxygenase activities, modification of the incubation conditions did not affect the non-cytochrome P-450 enzymatic activities.

Animals↗
PubMed1995

Renal toxicity after oral administration of lead acetate during pre- and post-implantation periods: effects on trace metal composition, metallo-enzymes and glutathione.

The present study was undertaken to compare the effects of 10-50 mg/kg b.wt. of Pb acetate after chronic treatment through oral gavage on: (a) the distribution of trace elements such as Fe, Cu, Zn, and Mn, (b) enzyme activity of delta-amino levulinic acid dehydratase (delta-ALAD) and alkaline phosphatase, and (c) glutathione (GSH) in kidney and (d) delta-ALAD in blood of pregnant and non-pregnant mice. Treatment with Pb acetate was given on every alternate day for 4 weeks prior to mating and for 3-4 weeks until pregnancy became apparent and confirmed by laporatomy. Lead administration reduced the rate of reproduction as assessed by number of living viable embryos. During normal pregnancy renal Cu, Fe and GSH tended to decline although non-significantly and continued to do so after lead administration. Mn was considerably and significantly elevated, whereas activity of delta-ALAD (non-activated) was quite low in pregnant mice. Following administration of Pb acetate, kidneys of pregnant and non-pregnant dams accumulated Pb in a dose-dependent manner, but as compared to non-pregnant mice, Pb increase in pregnant dams was significantly lower. Pb toxicity was associated with the loss of delta-ALAD in blood and kidney, but unlike the non-activated form of delta-ALAD, the dithiothreitol-activated form of delta-ALAD declined in a significant amount. The residual activity showed a high degree of negative correlation with endogenous Pb as well as with Zn/Pb ratio. Pb toxicity did not modify renal Fe, Cu, and Zn in the pregnant state, but reduced renal Fe during pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1998

Laser-based spectroscopic methods in tissue characterization.

Laser-based spectroscopic techniques were developed for tumor tissue characterization utilizing different tumor-localizing substances. In particular, sensitization with the heme precursor delta-amino levulinic acid (ALA) administered topically, orally or intravenously was used for the induction of protoporphyrin IX (PpIX). The autofluorescence as well as the PpIX-related fluorescence signals were monitored, and tumor demarcation functions were calculated for different human malignant tumors, such as tumors in the urinary bladder and the prostatic gland, in the head and neck region, in the breast and in the gastrointestinal tract. In the gastrointestinal tract, colon tumors were examined as well as tumors and dysplastic lesions in the esophagus, where patients with Barrett's esophagus were examined. Time-integrated laser-induced fluorescence measurements utilizing a point monitoring fluorosensor and a multicolor fluorescence imaging system were performed in vivo in patients in different clinical specialities.

Fluorescence↗
PubMed1988

Formation of the chlorophyll precursor delta-aminolevulinic acid in cyanobacteria requires aminoacylation of a tRNAGlu species.

In the chloroplasts of higher plants and algae, the biosynthesis of the chlorophyll precursor delta-aminolevulinic acid (ALA) involves at least three enzymes and a tRNA species. Here we demonstrate that in cell extracts of the unicellular cyanobacterium Synechocystis sp. strain PCC 6803 ALA was formed from glutamate in a series of reactions in which activation of glutamate by glutamyl-tRNAGlu formation was the first step. The activated glutamate was reduced by a dehydrogenase which displayed tRNA sequence specificity. Fractionation of strain 6803 tRNA by reverse-phase chromatography and polyacrylamide gel electrophoresis yielded two pure tRNAGlu species which stimulated ALA synthesis in vitro. These tRNAs had identical primary sequences but differed in the nucleotide modification of their anticodon. The 6803 tRNAGlu was similar to the sequences of tRNAGlu species or tRNAGlu genes from Escherichia coli and from chloroplasts of Euglena gracilis and higher plants. Southern blot analysis revealed at least two tRNAGlu gene copies in the 6803 chromosome. A glutamate-1-semialdehyde aminotransferase, the terminal enzyme in the conversion of glutamate to ALA in chloroplasts, was detected in 6803 cell extracts by the conversion of glutamate-1-semialdehyde to ALA and by the inhibition of this reaction by gabaculin.

Aminolevulinic Acid↗
PubMed1989

Transformation of glutamate to delta-aminolevulinic acid by soluble extracts of Chlorobium vibrioforme.

Formation of the tetrapyrrole pigment precursor delta-aminolevulinic acid (ALA) from glutamate was detected and partially characterized in extracts of the strictly anaerobic green photosynthetic bacterial species Chlorobium vibrioforme by using assay methods derived from those developed for algae and cyanobacteria. ALA formation in Chlorobium extracts was saturated at 10 mM glutamate and required NADPH and ATP at optimal concentrations of 0.3 and 3 mM, respectively. Preincubation of the enzyme extract with RNase A destroyed the ALA-forming activity completely. Activity in the RNase-treated extract was restored by supplementation with Chlorobium RNA after addition of RNasin to block further RNase action. RNA from the cyanobacterium Synechocystis sp. strain PCC 6803 and Escherichia coli tRNAGlu also restored activity. Activity was inhibited 50% by 0.2 microM hemin. ALA formation was completely abolished by the addition of 5 microM 3-amino-2,3-dihydrobenzoic acid (gabaculine). These results indicate that Chlorobium extracts share with those of plants, eucaryotic algae, cyanobacteria, prochlorophytes, and methanogens the capacity for RNA-dependent ALA formation from glutamate.

Aminolevulinic Acid↗
PubMed1995

Ferrochelatase activity and protoporphyrin IX utilization in Haemophilus influenzae.

Previous research showed that the heme-requiring human pathogen Haemophilus influenzae lacks the first six of the seven enzymes required for heme synthesis, starting with the precursor, 5-amino levulinic acid. In this study, I demonstrated either directly or by reasonable inference that all 57 strains of H. influenzae examined, including 2 unable to grow on protoporphyrin IX, possess ferrochelatase, which catalyzes heme formation by insertion of Fe2+ into the protoporphyrin IX nucleus and which is the last enzyme in the heme synthetic pathway. Further, I showed that this enzyme can also function in the reverse direction, releasing Fe2+ from heme.

Ferrochelatase↗
PubMed1978

Urinary kallikrein activity of workers exposed to lead.

Two groups of men of different age ranges and with the same period of lead exposure were selected for study in a recently opened car-battery factory. Two other groups of age-matched men, not exposed to heavy metals in their work, were used as controls. Morning urines were collected from control and exposed groups for determination of urinary kallikrein activity, urinary delta-amino-levulinic acid (ALA) and lead levels. The environmental lead levels and the urinary ALA and lead values indicated that exposure in the factory was not heavy. The older group of lead-exposed workers showed greatly reduced urinary kallikrein activity compared with that of the age-matched controls. In contrast, the younger group did not show any significant alteration in urinary kallikrein excretion.

Adult↗
PubMed1976

A compartmental model for bilirubin kinetics in isolated perfused rat liver.

Bilirubin kinetics were studied in an isolated, perfused rat liver system using unconjugated (14C) bilirubin (UC(14C)B) and delta-amino (4-14 C) levulinic acid (A(14 C)LA) to derive a suitable compartmental model. Plasma disappearance of UC(14C)B, plasma appearance of conjugated (14c) bilirubin (C(14C)B) and biliary excretion of C(14C)B were followed for 90-120 min following injection of UC(14C)B. Hepatic content of labeled bilirubin 12 min after the injection of UC(14C)B was determined directly in five separate perfusion experiments. UCB was found to reflux back to plasma from liver in two experiments using A(14C)LA. Bilirubin binding to red blood cells (6-8% of the perfusate level) and the components of the perfusion apparatus (4-6% of perfusate level) was estimated by performing a control experiment without the liver. A six compartment model was necessary and adequate to explain the experimental data and current knowledge of bilirubin metabolism: (1) UCB bound to red blood cells and the perfusion apparatus, (2) plasma UCB, (3) liver UCB, (4) liver CB, (5) plasma CB, and (6) bile CB. The proposed model could serve as a reference point for studies of bilirubin kinetics in whole animals for normal and abnormal states.

Aminolevulinic Acid↗
PubMed1999

New photosensitizers for photodynamic therapy in gastroenterology.

Most applications of photodynamic therapy (PDT) in gastroenterology to date have used porfimer sodium as the photosensitizing agent. For destroying small lesions in the wall of the gastrointestinal tract in inoperable patients, it has proved to be most effective, but attempts to achieve circumferential mucosal ablation, as in the treatment of Barrett's esophagus, have led to a high incidence of strictures, and all patients have cutaneous photosensitivity, which can last up to three months. Two new photosensitizers are of particular interest to gastroenterologists. PDT with metatetrahydroxyphenyl chlorin produces a similar biological effect as PDT with porfimer sodium, but the light doses required are much smaller, and cutaneous photosensitivity lasts only two to three weeks. Further, it can be used with percutaneous light delivery to destroy localized pancreatic cancers. The photosensitizing agent 5-amino levulinic acid, converted in vivo into the photoactive derivative protoporphyrin IX, sensitizes the mucosa much more than the underlying layers. This makes it feasible to destroy areas of abnormal mucosa without damaging the underlying muscle and is, therefore, better for treating Barrett's esophagus. Detailed clinical studies are required to establish the real role of PDT with the use of these and other new photosensitizers.

Aminolevulinic Acid↗
PubMed2002

The current diagnosis of superficial bladder cancer must be reconsidered.

The high recurrence and progression rates in superficial bladder cancer are partially related to the deficiencies of the standard conventional diagnostic modalities. Therefore, innovative noninvasive and invasive detection devices have been studied during the last decade. New diagnostic urine markers are under intensive investigation in order to exclude the presence of urothelial cancer, but the value of all these tests is still insufficiently validated in diagnosis and follow-up. With the introduction of 5-amino-levulinic acid fluorescence endoscopy, the efficacy of the detection device has been significantly improved. Flat lesions such as carcinoma in situ can be completely detected besides exophytic tumors. This is of particular importance because the fate of the patient depends to an important extent on these tumor entities. Furthermore, first experimental results using imaging devices like optical coherence tomography and confocal laser scanning microscopy promise new powerful noninvasive tools for 'optical sectioning' of the bladder.

Antigens, Neoplasm↗
PubMed1979

Hematin and propranolol in acute intermittent porphyria. Full recovery from quadriplegic coma and respiratory failure.

The authors present a case of acute intermittent porphyria (AIP) in an almost fatal relapse with quadriplegia, bulbar paralysis and coma. Intravenous hematin produced an immediate arousal from coma and allowed a gradual resumption of bulbar and autonomic functions. Persistent tachycardia and hypertension necessitated huge doses of intravenous propranolol. Both hematin and propranolol administrations were followed by a remarkable decrease in urinary amino-levulinic acid and porphobilinogen excretion. Nevertheless, after the acute stage, the patient was left with a severe generalized muscle wasting. After 7 months of intensive physical therapy, complete recovery of all neuromuscular functions was achieved. The modern aspects of the management of AIP are presented; the efficacy and the limits of hematin and propranolol therapy are discussed.

Acute Disease↗
PubMed1980

Degradation of endogenous hepatic heme by pathways not yielding carbon monoxide. Studies in normal rat liver and in primary hepatocyte culture.

The conversion of endogenous hepatic heme to bilirubin and CO is established. However, it is unknown whether this process is quantitative or whether heme may be degraded to other products as well. To study this question, we administered the heme precursor, delta-amino-[5-14C]levulinic acid to rats in vivo. In liver, [14C]heme was predominately associated with microsomal cytochromes, and its degradation was examined over a period of 12--14 h; concurrently, excretion of labeled carbon monoxide 14CO by the animal was measured. After correction for 14CO derived from the breakdown of renal [14C]heme, the rate of heme degradation calculated from the 14CO excreted was substantially less than the rate of disappearance of hepatic [14C]heme measured directly. The discrepancy between actual loss of labeled heme from the liver and generation of labeled CO was confirmed by direct study of endogenous [14C]heme degradation in primary hepatocyte culture, in which only 25% of the labeled heme disappearing during the incubation was converted to 14CO. By contrast, cultured cells converted exogenous [14C]heme nearly quantitatively to 14CO. We conclude that heme associated with microsomal cytochromes in normal rat liver is degraded substantially by non-CO forming processes.

Animals↗
PubMed1982

Metabolism of heme and bilirubin in rat and human small intestinal mucosa.

Formation of heme, bilirubin, and bilirubin conjugates has been examined in mucosal cells isolated from the rat upper small intestine. Intact, viable cells were prepared by enzymatic dissociation using a combined vascular and luminal perfusion and incubated with an isotopically labeled precursor, delta-amino-[2,3-3H]levulinic acid. Labeled heme and bile pigment were formed with kinetics similar to those exhibited by hepatocytes. Moreover, the newly formed bilirubin was converted rapidly to both mono- and diglucuronide conjugates. In addition, cell-free extracts of small intestinal mucosa from rats or humans exhibited a bilirubin-UDP-glucuronyl transferase activity that was qualitatively similar to that present in liver. The data suggest that the small intestinal mucosa normally contributes to bilirubin metabolism.

Aminolevulinic Acid↗
PubMed2002

The application of electroporation to transfect hematopoietic cells and to deliver drugs and vaccines transcutaneously for cancer treatment.

Electroporation and the associated phenomenon of electrofusion have been widely adapted as tools to a broad range of biomedical research and therapy. In this article, we summarize our adaptation of the electroporation and electrofusion technology in two fronts of cancer research and treatment. The first is genetic manipulation of hematopoietic cells for the purpose of cancer treatment. High efficiency transfection methods have been developed to transfect NK cells, peripheral blood stem cells, and bone marrow derived dendritic cells. Hybrids of tumor cells and bone marrow derived dendritic cells have been formed by electrofusion for the purpose of tumor vaccines. The second front is the use of transcutaneous electroporation to deliver anticancer drugs and vaccines across the skin. Methods to extend the upper molecular weight limit of transcutaneous electroporation have been developed. The pro-photosensitizer drug, delta-amino levulinic acid, the anticancer drug methotrexate, and peptide vaccines designed for cancer prevention and immunotherapy have been delivered transcutaneously by electroporation. These studies hold promise for the treatment of cancers in human.

Administration, Cutaneous↗
PubMedDate not supplied

Structure and expression of the CYP21 (P450c21, steroid 21-hydroxylase) gene with respect to its deficiency.

Steroid 21-hydroxylase (P450c21) deficiency is the major cause of a common genetic disease, congenital adrenal hyperplasia, with the symptoms of virilization due to steroid imbalance. We have devised a fast diagnostic method to detect common mutations in the c21B gene by a two-step gene amplification procedure coupled to restriction digestion. This procedure does not require isotopes and is suitable for routine use in a hospital setting. In addition, we have developed a procedure for the production of active P450c21 in E. coli. We tested many different vector and bacterial strain combinations to find out the best condition for P450c21 expression. The bacteria harboring the P450c21 expression plasmid were grown in a rich media supplemented with trace metals, heme biosynthesis precursor delta-levulinic acid, and induced with IPTG at 20 degrees C for 48 h. We found that low growth temperature and long induction time were important for abundant synthesis of P450c21 in E. coli.

Adrenal Hyperplasia, Congenital↗
PubMed1991

Marginal zinc deficiency and changes in behavioral salt taste threshold and salt preference in mice.

An animal model of marginal zinc deficiency was tested in mice, and salt taste threshold and salt preference were investigated in the state of marginal zinc deficiency. Two experiments were conducted. In Experiment 1, four-week-old male ICR mice were fed diets of three different levels of zinc content (3.17, 9.27, or 48.13 micrograms Zn/g) for 60 days. Food intake, growth, zinc levels in tissues, hepatic metallothionein (MT) content, and activities of selected enzymes (hepatic and RBC delta-amino-levulinic acid dehydratase (ALAD) and plasma alkaline phosphatase (ALP] did not differ among the groups throughout the experiment, and no overt signs of zinc deficiency were manifested in any group. In Experiment 2, four-week-old male ICR mice were fed a zinc-deficient diet (1.98 micrograms Zn/g) or a zinc-adequate diet (49.14 micrograms Zn/g) for 56 days. Food intake and growth did not differ between the two groups, and no overt signs of zinc deficiency were observed throughout the experiment. Zinc levels in the plasma and femur--but not those in the brain, kidneys, liver, and red blood cell (RBC)--and plasma ALP activities were significantly lower on Day 42 and Day 56 of the experiment in the mice fed the zinc-deficient diet (ZnD group) than in those fed the zinc-adequate diet (ZnA group). Hepatic MT contents were lower in the ZnD group than in the ZnA group on Day 56 only. Salt taste threshold was 0.05% in the ZnA group, while it was 0.1% in the ZnD group, between Day 30 and Day 38, and between Day 44 and Day 52 of the experiment. Preference for 0.9% NaCl solution was no different in the two groups when tested between Day 38 and Day 40 or between Day 52 and Day 54, but that for 1.6% NaCl solution was significantly higher in the ZnD group than in the ZnA group between Day 40 and Day 42, and between Day 54 and Day 56.

Alkaline Phosphatase↗