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Biomedical subjects

A Kappas

Publications and source records attributed to A Kappas.

At least 253 records · Page 14Linked to original sources
PubMed1978

[Nonocclusive vascular insufficiency of the bowel (author's transl)].

The particular problems of nonocclusive mesenteric vascular insufficiency are discussed on the basis of reports in the literature and 4 patients observed by the authors. Diminution in splanchnic blood flow as a manifestation of splanchnic compensation to low cardiac output seems to be the most common cause. The symptoms are described and the necessity for early diagnosis and immediate treatment are stressed. Our results of treatment in 4 patients with nonocclusive mesenteric vascular insufficiency are presented.

Aged↗
PubMed1977

Metals as regulators of heme metabolism.

Heme is essential for cell respiration, energy generation, and oxidative biotransformations. The latter function is exemplified by the oxidative metabolism of various endogenous and exogenous chemicals catalyzed by the heme protein cytochrome P-450. Recent studies have established that metal ions directly regulate cellular content of heme, and thus of heme proteins by controlling production of delta-aminolevulinate synthetase and heme oxygenase, the rate-limiting enzymes for heme synthesis and degradation, respectively. Metal ions also alter cellular content of glutathione. In excess amounts, metal ions greatly accelerate the turnover and degradation of heme and substantially impair the oxidative functions of cells--particularly those dependent on cytochrone P-450. As a result, the biological impact of chemicals which are detoxified or metabolically transformed by the P-450 system is greatly altered.

5-Aminolevulinate Synthetase↗
PubMed1977

Enzymes of heme metabolism in the kidney: regulation by trace metals which do not form heme complexes.

The in vivo regulation by metal ions of the enzymes of heme metabolism in kidney-particularly of ALAS, the rate-limiting enzyme in heine formation- was investigated. Ni(2+) and Pt(4+), metals which do not enzymatically form metalloporphyrins, were found to regulate ALAS in kidney as they do in liver. The pattern of this regulation was generally similar to that observed with heme and metal ions in liver, i.e., a late increase in enzyme activity after an early period in which ALAS activity was unaltered or inhibited. The metals did not interact with the enzyme in vitro to alter its activity. In this study no direct reciprocal relationship between ALAS activity and total cellular heine content was demonstrated. The metal ions, particularly Pt(4+), also altered the activity of other enzymes of heme biosynthesis in kidney. Pt(4+) severely inhibited the activity of ALAD and UROS. Ni(2+) and Pt(4+) were potent inducers of heme oxygenase, the initial and rate-limiting enzyme in heine degradation. It is proposed that the physiological regulation of ALAS is mediated through the action of metal ions, rather than by the cellular content of heine, and that the regulation of ALAS by heine reflects the action of the central metal ion of heme rather than that of the entire metalloporphyrin complex. In this proposed mechanism for metal ion regulation of ALAS, the tetrapyrrole moiety of heine is considered to function principally as an efficient carrier of metal to the regulatory site for ALAS production, inasmuch as the tetrapyrrole ring itself has been shown in earlier studies not to have any effect on ALAS activity. The production of heine oxygenase is believed to be similarly regulated.

5-Aminolevulinate Synthetase↗
PubMed1977

Solubilization and partial purification of heme oxygenase from rat liver.

Hepatic microsomal heme oxygenase was solubilized, partially purified, and characterized from Co2+-treated rats. The enzyme on sodium dodecyl sulfate-polyacrylamide gel electrophoresis exhibited a minimum molecular weight of greater than or equal to 68,000. The solubilized enzyme was totally devoid of contamination with cytochrome P-450 or b5. The requirement for reduced pyridine nucleotides was absolute, and ascorbate could not support heme oxidative activity. However, both TPNH and DPNH could serve as electron donors, with TPNH being more effective. The presence of an appropriate flavoprotein reductase was essential for heme oxidation. The enzyme had an apparent Km of 40 micrometer, a pH optimum of 7.5, and lost substantial activity upon freezing and thawing. Methemoglobin was 30% as effective a substrate for the enzyme as was heme. Free porphyrins could not serve as substrates for the enzyme. The activity of the enzyme was inhibited by HgCl2, p-chloromercuribenzoate, iodoacetamide, mercaptoethanol, and dithiothrietol indicating that free -SH group(s) is necessary for enzyme activity.

Animals↗
PubMed1977

On the occurrence of cytochrome P-450 and aryl hydrocarbon hydroxylase activity in rat brain.

The difference spectra of the carbon monoxide-complex of dithionite-reduced rat brain microsomes, compared with both reduced microsomes, alone, and the carbon monoxide-complex of oxidized microsomes, indicate the presence of small amounts of cytochrome P-450 in brain. As in liver, cytochrome P-450 in brain is degraded in vitro to its inactive form, cytochrome P-420 by methylmercury chloride. Aryl hydrocarbon hydroxylase activity is also present in rat brain microsomes and, at lower specific activity, in brain homogenates. This carcinogen metabolizing activity is increased four-fold in rats pretreated with 3-methylcholanthrene.

Animals↗
PubMed1977

Induction of aminolevulinate synthase and porphyrins in cultured liver cells maintained in chemically defined medium. Permissive effects of hormones on induction process.

Primary liver cells, isolated from 16- 17-day-old chick embryos, were incubated in a serum-free chemically defined medium (Ham's F12) supplemented with hormones for up to 6 days. The culture method also includes the complete removal of contaminating red cells before the initiation of culture. On the 2nd day in cluture, the level of amino-levulinate (ALA) synthase activity in response to allylisopropylacetamide (AIA) was increased 6-fold in cells grown in F12. Insulin, hydrocortisone, and triiodothyronine alone had no appreciable effects on ALA synthase levels. On the other hand, when added with AIA, insulin, insulin plus hydrocortisone, insulin plus hydrocortisone triiodothyronine increased ALA synthase levels 17-, 50-, 110-fold, respectively. The maximally induced levels of ALA synthase activity by AIA in the presence of insulin, hydrocortisone, and triiodothyronine were approximately 15 nmol of ALA/mg of protein/h, 37 degrees or 3 micronmol of ALA/g of tissue/h, 37 degrees, a value similar to that found in ovo or at least 5 times greater than that found in rat liver. The morphology of hepatocytes was maintained for at least 6 days in culture, although the induction of ALA synthase was reduced after the 4th day unless triiodothyronine was present. Dibutyryl adenosine 3':5'-monophosphate (10(8) M) or glucagon (5x10(8) M) had little effect on the induced as well as noninduced levels of ALA synthase or porphyrins. These data demonstrate a "permissive" effect of insulin, hydrocortisone, and triiodothyronine on the induction of ALA synthase and porphyrins by AIA in cultured chick embryo liver cells. In the absence of insulin hydrocortisone, or triiodothyronine, AIA produces only a slight increase in ALA synthase activity or porphyrins (or both); on the other hand, it produces a marked increase in the enzyme activity and porphyrins when these hormones are added to the culture medium. The term "permissive" is applied to these hormone-dependent effects. A sensitive spectrofluorometric method for heme quantitation allowed us to follow changes in the cellular heme content in hemoglobin-free cultured liver cells. Heme content in the cultured liver cells was approximately 250 pmol/mg of protein at the initiation of culture but gradually declined to 175 pmol/mg of protein at the initiation of culture but gradually declined to 175 pmol/mg of protein during 48 h of incubation. The apparent decrease in heme content may be accounted for by the concomitant increase in protein content in these cells.

5-Aminolevulinate Synthetase↗
PubMed1977

Enzymatic oxidation of cobalt protoporphyrin IX: observations on the mechanism of heme oxygenase action.

Studies on the enzymatic mechanism of microsomal heme oxygenase were made utilizing various porphyrins and metalloporphyrins of different ring substituents and central metal ions. Co-heme (cobalt protoporphyrin IX) was shown to be a substrate for the enzyme and the product of its oxidative metabolism was identified as the natural bile pigment, biliverdin IXalpha isomer. Metalloporphyrins, which do not bind molecular oxygen (Ni, Mn, and Sn protoporphyrin IX), were not substrates for heme oxygenase, although they could competitively inhibit oxidation of reactive substrates for the enzyme. The presence of lipophilic substitutents on pyrrole rings I and II, as well as a central metal atom, were required for the heme oxidation reaction to occur. The oxidative cleavage of Co-heme displayed typical characteristics of an enzyme-mediated reaction, and the oxidation of this substrate, as well as that of Fe-heme (iron protoporphyrin IX), could be supported with either reduced nicotinamide adenine dinucleotide phosphate or reduced nicotinamide adenine dinucleotide. A hypothesis is proposed on the mode of action of heme oxygenase in which the enzyme and its substrate are considered to form a "transitory" hemoprotein which can activate molecular oxygen for cleavage of the heme tetrapyrrole ring. In this formulation, heme as substrate for heme oxygenase is synonymous with heme as prosthetic group for the enzyme.

Animals↗
PubMed1977

Alterations in drug metabolism in workers exposed to polychlorinated biphenyls.

Administration of the polychlorinated biphenyls (PCBs) mixture, Aroclor 1016, to rats elicited a barbiturate type of inducing effect on the hepatic microsomal oxidative enzyme system. Aroclor 1016 caused significant increases in liver cytochrome P-450 content, microsomal protein, and ethylmorphine N-demethylase activity; its effect on benzo(a)pyrene hydroxylase activity was minimal. Unlike the widely studied PCBs mixture, Aroclor 1254, Aroclor 1016 did not induce cytochrome P-448 in liver microsomes. Five workers occupationally exposed to Aroclor 1016 in a capacitor-manufacturing plant showed a significantly lower mean antipyrine half-life (10.8 hr) than the mean half-life of 15.6 hr in non-PCBs-exposed normal subjects. These differences in half-life were accompanied by increased metabolic clearance rates in workers exposed to the PCBs, which strongly suggests that PCBs accelerate the rate of drug metabolism in man. Our studies show that Aroclor 1016 elicits the barbiturate type of inducing effects on drug metabolism in man as well as animals.

Adult↗
PubMed1977

Regulation of cytochrome P-450-dependent microsomal drug-metabolizing enzymes by nickel, cobalt, and iron.

The effects of metals as modifiers of the activity of microsomal drug-metabolizing enzymes were studied with the use of nickel, cobalt, and iron. These metals were found to impair cellular heme-dependent metabolism by affecting both the heme biosynthetic and heme degradative pathways, inhibiting the former and inducing the latter. As powerful cellular toxins, metals depress respiratory activity and indirectly reduce drug-detoxifying ability of cells. Metals also perturb cellular glutathione content and thus may alter the activity of glutathione-dependent enzymes. The toxicity of metals is cumulative depending on concentration and degree of cellular exposure to one or to several closely related metals. On the other hand, these metal effects on cellular heme metabolism could also have selective therapeutic application in circumstances in which it may be desirable to suppress heme synthesis in order to decrease drug biotransformation, i.e., when a certain drug metabolite is more toxic than the parent compound.

Animals↗
PubMed1977

The inducing properties of polychlorinated biphenyls on hepatic monooxygenases.

The polychlorinated biphenyls (PCBs) represent a newly recognized and widely distributed category of environmental pollutants whose biologic impact on animals and man may be both substantial and highly detrimental. The pharmacologic effects of these agents on enzymes in the liver which metabolize drugs and other foreign compounds, such as carcinogens, are powerful and long lasting. PCBs mimic the effects produced on these enzymes by drugs, such as phenobarbital, and carcinogens, such as 3-methylcholanthrene. They are potent inducers of cytochromes P-45O and P-448 and associated enzymic activities. Further, these chemicals can cross the placental barrier and be transmitted through maternal milk to the newborn infant causing marked increases in drug biotransformation enzymes in the fetus and the neonate. Studies with the use of microscope immersion oils containing PCBs show that application of minute amounts of these oils to the skin of experimental animals results in a marked induction of the drug-and carcinogen-metabolizing enzymes. These findings suggest that even trivial skin exposure to chemicals, such as PCBs, can have significant and perhaps harmful biologic effects in man.

Animals↗
PubMed1977

Regulation of heme pathway enzymes and cellular glutathione content by metals that do not chelate with tetrapyrroles: blockade of metal effects by thiols.

The trace metals nickel and platinum, which are not substrates for ferrochelatase and thus do not form heme in biological systems, were found to act similaryl to cobalt, and heme itself, in regulating heme metabolism in liver and kidney. These metals induced heme oxygenase activity in both organs with the peak of induced enzyme activity reached approximately 16 hr after single injections in rats. Both metals caused transient depression of cellular glutathione content followed by increases above normal after 12 hr in liver. Nickel and platinum were more potent inducers of heme oxygenase in kidney than in liver (10-13 times normal versus 5-6 times normal). At high concentrations, they inhibited heme oxygenase [heme, hydrogen-donor:oxygen oxidoreductase (alpha-methene-oxidizing, hydroxylating), EC 1.14.99.3] in vitro. Both were active in regulating heme metabolism only when administered in the ionic form. Complexing of the metals with sulfhydryl agents completely blocked their actions on heme metabolism. Administration of cysteine orally prior to or shortly after administration of the metals had a similar blocking effect. Nickel and platinum produced depression of delta-aminolevulinate synthase [succinyl-CoA:glycine c-succinyltransferase (decarboxylating), EC 2.3.1.37] activity in liver, but neigther inhibited this rate-limiting ennzyme for heme synthesis in vitro. Furthermore, despite the substantial decreases in cellular heme and hemoprotein contents mediated by the metal, production of delta-amimolevulinate synthase did not undergo the compensatory increase that would be expected if there were a direct reciprocal feedback relationship between cellular heme level and synthesis of this enzyme. These findings indicate that it is not necessary for metal ions to be chelated in the porphyrin ring in order to regulate the enzymes of heme synthesis and heme oxidation. Accordingly, it is suggested that the iron atom of heme is the proximately active regulator of delta-aminolevulinate synthase and heme oxygenase--actions generally ascribed to the iron-tetrapyrrole complex itself--and that the tetrapyrrole moiety of the complex functions primarily as a means of transport of the metal to regulatory sites in cells.

5-Aminolevulinate Synthetase↗
PubMed1977

Lead intoxication among demolition workers: the effect of lead on the hepatic cytochrome P-450 system in humans.

Overt clinical disease from undue lead exposure has become a relatively rare phenomenon in adult populations. However, exposure situations that may result in subclinical disease are not uncommon in various occupational settings. Five demolition workers, dismantling an old iron structure covered with lead-content paint, were studied. The use of cutting torches resulted in lead fumes, with significant exposure, albeit without gross 'lead poisoning." All five workers showed biochemical manifestations of chronic lead intoxication-that is, elevated blood lead level, inhibition of delta-aminolevulinic acid dehydratase (ALA-D), and elevated erythrocytic protoporphyrin concentration (PROTO). The effect of lead on the biosynthesis of heme was assessed by investigating the functional capacity of the cytochrome P-45O system of the liver, through drug metabolism studies. The plasma elimination rates (half-lives) of antipyrine and phenylbutazone-drugs primarily metabolized by the hemeprotein P-450 dependent hepatic microsomal enzyme system-were measured before and after chelation therapy. Prior to chelation therapy all half-lives were within the normal range. A slight decrease in the half-life of antipyrine was found after treatment. These studies show that chronic exposure to lead has only a minimal effect on hepatic cytochrome p-450 dependent enzymatic activities in adult males.

Adult↗