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Biomedical subjects

A Kappas

Publications and source records attributed to A Kappas.

At least 181 records · Page 10Linked to original sources
PubMed1984

An experimental model of postnatal jaundice in the suckling rat. Suppression of induced hyperbilirubinemia by Sn-protoporphyrin.

A model of experimental postnatal hyperbilirubinemia in the rat has been developed utilizing the heme precursor delta-aminolevulinic acid (ALA) to produce jaundice during a selective time period after birth. This time period is defined as that between 7 d postnatally, when the initial postpartum alterations of serum bilirubin and heme metabolism in the neonate have subsided, and 21 d, when the hepatic conjugation mechanism for the bile pigment appears fully developed. Administration of ALA in this time period led to a rapid, consistent, and significant dose-dependent increase in serum bilirubin levels in the newborn animals. Heme administration produced a qualitatively similar but enhanced effect. Both compounds, in addition, induced a dose-dependent increase in hepatic heme oxygenase activity concomitant with the increase in serum bilirubin levels. Neither compound increased serum bilirubin levels significantly when administered at or after 21 d postnatally. Administration of the synthetic metalloporphyrin, Sn-protoporphyrin, to ALA-treated neonates resulted in a dose-dependent decrease in serum bilirubin levels and hepatic heme oxygenase activity. Mn- and Zn-protoporphyrin in comparable doses did not significantly inhibit ALA-induced hyperbilirubinemia. Sn-protoporphyrin also inhibited the hyperbilirubinemia produced by heme in the suckling animals. ALA administration to newborn rats during the specific postnatal period described provides a simple and convenient model of experimental jaundice in the developing neonate which permits an examination of the potential ability of synthetic metalloporphyrins or other compounds to suppress induced hyperbilirubinemia in the newborn animal. The ability to induce a consistent and significant degree of jaundice in the postnatal rat by the method described may also be useful for other types of studies concerned with the biological disposition and effects of endogenously formed bilirubin in the neonate. The results of this study confirm in another model system the potent ability of Sn-protoporphyrin to suppress jaundice in the neonate, and suggest that suppression of heme oxidation by synthetic heme analogues may represent a useful therapeutic approach to the problem of severe hyperbilirubinemia in human premature newborn.

Aging↗
PubMed1984

Porphyrin-heme biosynthesis in organotypic cultures of mouse dorsal root ganglia. Effects of heme and lead on porphyrin synthesis and peripheral myelin.

Well-myelinated cultures of mouse dorsal root ganglia incubated for 48 h with sigma-aminolevulinic acid (ALA) showed intense porphyrin fluorescence localized in myelin sheaths but not in axons or neuronal somata. When the cultures were continuously incubated with a high concentration of lead, focal swelling and segmental degeneration of myelin began to develop within 2 wk. Incubation of cultures with ALA after 3 wk of lead treatment revealed markedly decreased porphyrin fluorescence in myelin sheaths compared with untreated controls. After 6 wk of lead treatment, myelin showed severe segmental degeneration. Porphyrin fluorescence from ALA at this time was barely detectable in these cultures. No fluorescence was visible in the demyelinated axons; however, silver-impregnation staining after fixation demonstrated continuity of the axon despite the severe loss of myelin. When cultures were continuously incubated with lead and heme together for 6 wk, the segmental demyelination seen in cultures treated with lead alone did not occur. These findings suggest that the lead-induced segmental demyelination in cultured mouse dorsal root ganglia may be due to toxic effects of the metal on the heme biosynthetic pathway in myelinating cells and that exogenous heme may counteract this toxic effect of lead.

Aminolevulinic Acid↗
PubMed1984

The influence of dietary protein and carbohydrate on the principal oxidative biotransformations of estradiol in normal subjects.

Dietary protein, when substituted for carbohydrate or fat, can increase cytochrome P-450-dependent drug oxidation rates in humans. Endogenous estrogens, as well as drugs, are also metabolized by cytochrome P-450 and other enzymes in the hepatic endoplasmic reticulum. Therefore, it was of interest to determine whether variations in diet can alter the major metabolic pathways for estrogens, as assessed by radiometric methods. Eight normal men were fed a high protein diet (44% of calories as protein, and 35% as carbohydrate for 2 weeks), followed by a high carbohydrate diet (70% of calories as carbohydrate and 10% as protein) for an additional 2 weeks. The fat and total energy contents of the two diets were equal. The percent oxidation of [2-3H]estradiol, measured as 3H2O released, which is an in vivo measure of 2-hydroxylation of endogenous estrogen, was greater in all eight men during the high protein dietary period than during the high carbohydrate dietary period (44 +/- 3% and 33 +/- 3%, respectively, means +/- SE, P less than 0.005). In contrast, 16 alpha-hydroxylation of estrogen, as measured using [16 alpha-3H]estradiol, did not change significantly. Our findings demonstrate that dietary components can alter estradiol oxidation in humans and that the 2- and 16 alpha-hydroxylases for estrogen are under separate regulatory control. The influences of specific nutrients on estrogen metabolism may have potential significance for diseases in which these hormones may play a role in clinical expression.

Antipyrine↗
PubMed1984

Control of heme and cytochrome P-450 metabolism by inorganic metals, organometals and synthetic metalloporphyrins.

The heme-cytochrome P-450 complexes represent sensitive metabolic systems for examining the biological impact of metals on important cellular functions. Many metals, both in the inorganic form and bound to organic moieties, potently induce heme oxygenase, the rate limiting enzyme of heme degradation. The resulting increase in the rate of heme breakdown is reflected in a marked depression of cellular cytochrome P-450 content and impairment of the oxidative metabolism of natural and foreign chemicals dependent on this hemeprotein. Organometal complexes do not mimic in all their aspects the actions of the inorganic elements which they contain. For example, organotins, in contrast to inorganic tin, produce a prolonged induction response of heme oxygenase in the liver but not in the kidney. Co-protoporphyrin is a much more potent inducer of heme oxygenase in liver than is inorganic cobalt; and Sn-protoporphyrin inhibits heme oxygenase activity nearly completely, whereas inorganic tin is a powerful inducer of the renal enzyme. Contrasting effects on heme metabolism exist as well within the metalloporphyrin species as demonstrated by the effects in vivo of Co-protoporphyrin and Sn-protoporphyrin on heme oxygenase activity; the former induces the enzyme whereas the latter potently inhibits it. In vitro, however, both compounds competitively inhibit heme oxidation activity. These differences, among others which characterize metal actions in vivo and in vitro attest to the importance of pharmacokinetic, adaptive and other host factors in defining the responses of the heme-cytochrome P-450 systems to the impact of metals in the whole animal.

Animals↗
PubMed1984

Tissue distribution and disposition of tin-protoporphyrin, a potent competitive inhibitor of heme oxygenase.

Tin(Sn)-protoporphyrin is a potent competitive inhibitor of heme oxygenase and can also suppress naturally occurring or experimentally induced hyperbilirubinemia in animals. In this study we examined the plasma clearance of Sn-protoporphyrin, its persistence in tissues and the time course of heme oxygenase inhibition up to 7 days after administration of doses up to 50 mumol/kg b.w. to adult male rats. After s.c. doses the metalloporphyrin was rapidly and almost completely absorbed. Initial plasma clearance was log-linear with a T 1/2 of approximately 3 h after either i.v. or s.c. administration. Levels of Sn-protoporphyrin in most tissues rose during the first 2 h and persisted for up to 7 days. Concentrations were highest in kidney and liver, were considerably lower in spleen, lung, intestine, adrenal and testes, and as Sn-protoporphyrin concentrations in plasma declined, concentrations in these tissues eventually exceeded simultaneous plasma concentrations. This suggests a varying degree of uptake and binding of the metalloporphyrin in these tissues. There was little or no uptake of Sn-protoporphyrin in heart, brain and red cells. Markedly decreased heme oxygenase activity in liver, kidney and spleen persisted as did Sn-protoporphyrin up to 7 days. The total amount of Sn-protoporphyrin present in tissues and excreta was a fairly constant fraction of the dose (approximately 50%) at time intervals up to 7 days after injection. These results indicate that single doses of Sn-protoporphyrin are rapidly cleared from plasma and persist in tissues and potently inhibit heme oxygenase activity for prolonged periods.

Animals↗
PubMed1983

Effects of polychlorinated biphenyl compounds, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phenobarbital and iron on hepatic uroporphyrinogen decarboxylase. Implications for the pathogenesis of porphyria.

Treatment of cultured chick embryo hepatocytes with phenobarbital, polychlorinated biphenyl compounds and 2,3,7,8-tetrachlorodibenzo-p-dioxin resulted in increased delta-aminolaevulinate synthase and decreased uroporphyrinogen decarboxylase activities and porphyrin accumulation; uroporphyrin and heptacarboxyporphyrin predominated. Iron had no effect on these changes. Simultaneous treatment of cultures with dioxin and phenobarbital produced a synergistic response in delta-aminolaevulinate synthase induction, uroporphyrinogen decarboxylase inhibition and porphyrin accumulation. These data suggest that an inhibitor of uroporphyrinogen decarboxylase may be generated in the liver from polychlorinated biphenyl compounds or dioxin by metabolic activation. Additionally these findings bear on the postulated role of these and related chemicals in determining the low levels of uroporphyrinogen decarboxylase activity in porphyria cutanea tarda patients.

5-Aminolevulinate Synthetase↗
PubMed1983

Growth-promoting effects of iron- and cobalt- protoporphyrins on cultured embryonic cells.

The effects of hemin (Fe-protoporphyrin) and Co-protoporphyrin on cellular growth have been investigated principally in cultured fibroblasts, but also in myoblasts and hepatocytes from chick embryos. In the presence of horse serum in the culture medium, which by itself did not stimulate cell growth appreciably, Co-protoporphyrin stimulated cell attachment while hemin stimulated cell proliferation of fibroblasts. When Co-protoporphyrin and hemin were added together, the most potent stimulation of cell growth, consisting of increases in cell attachment and rapid cell proliferation, was observed. These findings indicate that the two metalloporphyrins have differential and complementary effects on cellular growth in culture, with synthetic Co-protoporphyrin principally affecting cellular attachment and Fe-protoporphyrin stimulating cellular proliferation.

Animals↗
PubMed1983

Acetaminophen metabolism in subjects fed charcoal-broiled beef.

The effects of consumption of charcoal-broiled beef on the metabolism of acetaminophen by conjugation were determined in nine normal subjects. We had reported that beef prepared in this manner accelerates the oxidative metabolism of drugs, including the oxidation of phenacetin to N-acetyl-p-aminophenol (acetaminophen). In nine normal subjects, a control diet was followed by a charcoal-broiled beef diet, which was followed by the control diet. The charcoal-broiled beef had little or no effect on the plasma-level profile of acetaminophen, acetaminophen glucuronide and acetaminophen sulfate, or on the urinary excretion of acetaminophen, acetaminophen glucuronide, acetaminophen sulfate, 3-methoxy-acetaminophen, or the cysteine and mercapturic acid conjugates of acetaminophen. Results indicate that the enzyme systems that conjugate acetaminophen in man are subject to little or no influence by charcoal-broiled beef. Therefore dietary factors that increase drug oxidations cannot be assumed to have a similar effect on drug conjugation.

Acetaminophen↗
PubMed1983

Nutrition-endocrine interactions: induction of reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-dependent oxidation of estradiol by dietary macronutrients in man.

The in vivo biotransformations of drugs known to be metabolized by enzymes localized in the endoplasmic reticulum of liver can be greatly altered by diet in humans, as we have shown previously. Steroid hormones also are metabolized extensively by hepatic microsomal enzymes; therefore, we examined the possibility that testosterone and estradiol biotransformations, as assessed with radiolabeled tracer methods, could be influenced by dietary macronutrients. Normal males were fed a high-protein diet for 2 weeks, followed by a high-carbohydrate diet for an additional 2 weeks. The delta 4-5 alpha-reduction of testosterone was considerably diminished, while the cytochrome P-450-dependent hydroxylation of estradiol at the C2 position was substantially enhanced during ingestion of the high-protein diet as compared with the high-carbohydrate diet. These results indicate that dietary macronutrients can significantly alter major metabolic pathways for testosterone and estradiol in man. The mechanism by which reciprocal changes in the delta 4-5 alpha-reduction of testosterone and the cytochrome P-450-mediated oxidation of estradiol are produced by diets is not known. Similar changes in steroid delta 4-5 alpha-reduction and cytochrome P-450-dependent chemical oxidations have been observed in circumstances in which the mixed-function oxidase system in liver is induced by agents such as phenobarbital, hexachlorobenzene, dioxin, and polyhalogenated biphenyls. Thus, the alterations in steroid hormone metabolism produced by dietary macronutrients in man mimic those that can be produced by drugs and environmental chemicals.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1983

Genotoxic activity of plant growth-regulating hormones in Aspergillus nidulans.

Three plant growth-regulating hormones, indole-3-acetic acid (IAA), indole-3-butyric acid (IBA), and kinetin (6-furfuryl-aminopurine), were tested for their genetic activity in Aspergillus nidulans in a plate test. The first two hormones were found to greatly increase somatic segregation in the fungus whereas kinetin was not effective. Several concentrations of the plant hormones were used and it was found that increasing concentrations of IAA and IBA increased mitotic segregation of the fungus with most of the segregants being produced by mitotic crossing-over, together with non-disjunctional segregants at a lower level. The metabolic activation technique was also used and it was shown that when S9 mixture was added to IAA and IBA a further 3- to 5-fold increase in the number of segregants was obtained. In the case of kinetin the S9 had no effect.

Aspergillus nidulans↗
PubMed1983

Sideroblastic anaemia associated with lincomycin therapy.

Sideroblastic anaemia developed after lincomycin therapy in a 58-year-old woman. The anaemia proved completely reversible after termination of lincomycin therapy and the introduction of pyridoxine. The patient also had pseudomembranous enterocolitis, a well-known side effect of lincomycin.

Anemia, Sideroblastic↗
PubMed1983

Hereditary tyrosinemia and the heme biosynthetic pathway. Profound inhibition of delta-aminolevulinic acid dehydratase activity by succinylacetone.

Succinylacetone (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase. It is known that patients with this hereditary disease excrete excessive amounts of delta-aminolevulinic acid (ALA) in urine and that certain patients have an accompanying clinical syndrome resembling that of acute intermittent porphyria (AIP). In order to elucidate the relation of succinylacetone to the heme biosynthetic pathway, we have examined the effects of this metabolite on the cellular heme content of cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse and bovine liver. Our data indicate that succinylacetone is an extremely potent competitive inhibitor of ALA dehydratase in human as well as in animal tissues. By using purified preparations of the enzyme from human erythrocytes and mouse and bovine liver, an inhibitor constant ranging from 2 x 10(-7) M to 3 x 10(-7) M was obtained. In cultured hepatocytes, succinylacetone also inhibited ALA dehydratase activity, decreased the cellular content of heme and cytochrome P-450, and greatly potentiated the induction response of ALA synthase to drugs such as phenobarbital, chemicals such as allylisopropylacetamide and 3,5-dicarbethoxy-1,4-dihydrocollidine, and natural steroids such as etiocholanolone. Four patients with hereditary tyrosinemia have been studied and all were found to have greatly depressed levels of erythrocyte ALA dehydratase activity and elevated concentrations of this inhibitor in urine. These findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone, an abnormal product of the tyrosine metabolic pathway, resulting from the primary gene defect of the disease, profoundly inhibits heme biosynthesis in normal cells through a blockade at the ALA dehydratase level, leading to clinical and metabolic consequences that mimic another genetic disease, AIP.

Amino Acid Metabolism, Inborn Errors↗
PubMed1983

Metabolism of estradiol in liver cell culture. Differential responses of C-2 and C-16 oxidations to drugs and other chemicals that induce selective species of cytochrome P-450.

The oxidative metabolism of estradiol (the natural estrogen 2,3,5(10)-estratriene-3,17 beta-diol) at positions C-2 and C-16 was examined in primary cultures of chick embryo liver cells using estradiol which was labeled with 3H specifically at either the C-2 or C-16 position as the substrate. Oxidation of estradiol by the cultured liver cells was assessed by the release of 3H which accumulated as 3H2O in the culture medium; both C-2 and C-16 oxidative reactions were detectable in the liver cell cultures by this technique. When incubated with a concentration of estradiol substrate close to the Michaelis constant (Km), approximately 45.8 pmol [2-3H]estradiol and 5.0 pmol [16-3H]estradiol/mg protein per minute underwent oxidative metabolism in untreated cells. Total amounts of oxidized product formation after 2 h of incubation were 28 and 5 pmol/mg protein for C-2 and C-16 oxidation, respectively. Treatment of cultures with phenobarbital or 2-propyl-2-isopropylacetamide significantly increased oxidation at C-16 (1.9-fold and 2.6-fold greater than control values, respectively), whereas no significant change in C-16 oxidation was observed after treatment of the cultures with 3-methylcholanthrene, benzo[a]pyrene, or benz[a]anthracene. The latter chemicals, however, were found to increase the extent of oxidation at C-2 significantly (i.e., 1.5-2.2-fold increases over control values). The increase in C-2 oxidation after treatment of cultures with phenobarbital or 2-propyl-2-isopropylacetamide was significantly less than that observed for oxidation at C-16. The apparent Km values for these oxidations in control cultures were 23.5 and 30.3 microM for C-2 and C-16 oxidation, respectively; corresponding maximum velocity (Vmax) values were 119 and 11.7 pmol/mg protein per minute, respectively. These data indicate that the C-2 and C-16 oxidations of estradiol take place in cultured avian hepatocytes and that the extent of metabolism at these positions on the hormone molecule can be altered by chemicals, such as drugs and polycyclic aromatic hydrocarbons, which induce distinctive species of cytochrome P-450 in the liver.

Allylisopropylacetamide↗
PubMed1983

Purification and properties of human erythrocyte uroporphyrinogen decarboxylase: immunological demonstration of the enzyme defect in porphyria cutanea tarda.

The first complete purification of UROD from human erythrocytes and the characterization of the purified enzyme were described. A single enzyme protein catalyzes the four successive sequential decarboxylations of uroporphyrinogen to yield coproporphyrinogen. The enzyme activity is not directly inhibited by iron; however, it is subject to inhibition in liver cells by a number of chemicals, including environmental pollutants such as dioxin. Studies of erythrocyte UROD in PCT patients indicate that the group of patients now defined as having sporadic PCT may represent two different populations; i.e., those who have normal UROD, and those who have decreased UROD in erythrocytes. Genetic heterogeneity of the UROD defect in PCT is also indicated by the identification of both CRM(-) and CRM(+) mutations in this disorder.

Amino Acids↗
PubMed1983

Tin-protoporphyrin suppression of hyperbilirubinemia in mutant mice with severe hemolytic anemia.

Tin-protoporphyrin is a potent competitive inhibitor of heme oxygenase both in vivo in animals and in vitro in isolated enzyme preparations, and when administered to neonatal rats, prevents the development of postnatal hyperbilirubinemia. In this study we examined the effect of the metalloporphyrin on the activity of heme oxygenase in liver, kidney, and spleen, and on the level of bilirubin in plasma in three types of anemic mutant mice with severe hemolytic diseases. We report that the administration of tin-protoporphyrin to anemic mutants homozygous for severe hemolytic disease results in substantial inhibition of heme oxidation in liver, spleen, and kidney and in significant reduction of plasma bilirubin levels. Tin-protoporphyrin thus has the capacity to significantly inhibit in vivo heme degradation and to concurrently diminish plasma bilirubin levels in severe chronic hemolytic disorders.

Anemia, Hemolytic↗
PubMed1982

Suppression of hyperbilirubinemia in the rat neonate by chromium-protoporphyrin. Interactions of metalloporphyrins with microsomal heme oxygenase of human spleen.

The synthetic metalloporphyrin, Cr-protoporphyrin, as a potent competitive inhibitor of heme oxygenase activity in rat spleen, liver, and kidney. When administered to neonatal animals in a single dose immediately after birth, Cr-protoporphyrin suppresses postnatal hyperbilirubinemia and produces a marked and sustained lowering of heme oxidation activity in liver, spleen, and kidney. The metalloporphyrin also potently inhibited the rate of heme degradation to bile pigment in human spleen.

Animals↗
PubMed1982

Chemoprevention of neonatal jaundice: potency of tin-protoporphyrin in an animal model.

The substantial increases of hepatic, splenic, and renal heme oxygenase levels that occur shortly after birth in neonatal rats were prevented by a single administration of tin-protoporphyrin (10 micromoles per kilogram of body weight). With this treatment serum bilirubin levels declined within 24 hours to near-normal adult levels and remained low throughout the postnatal period. Zinc-protoporphyrin at doses up to 50-fold greater than the effective dose of tin-protoporphyrin did not prevent the immediate increases in tissue heme oxygenase activities and in serum bilirubin levels that occur postnatally. Studies in vitro with microsomal heme oxygenase in human spleen indicate that tin-protoporphyrin is a potent competitive inhibitor of the oxidation of heme to bile pigment in this tissue.

Animals↗