Search PubMed⌕ Search

Biomedical subjects

A Kappas

Publications and source records attributed to A Kappas.

At least 289 records · Page 16Linked to original sources
PubMed1976

Interactions between nutritional factors and drug biotransformations in man.

This study was undertaken to examine the influence of nutritional factors on the activity of the mixed function oxidase system in man, which is cytochrome P-450 dependent. Three normal volunteers were fed a low carbohydrate-high protein diet for 2 weeks, followed by a high carbohydrate-low protein diet for the follwoing 2 weeks. At the end of each test diet period, the plasma elimination rates of antipyrine and theophylline were determined. The mean plasma half-life for antipyrine was 17.5 hr on the high carbohydrate-low protein diet and 9.2 hr on the low carbohydrate-high protein diet. The mean plasma half-life for theophylline was 8.9 hr on the high carbohydrate-low protein diet and 5.9 hr on the low carbohydrate-high protein diet. These data demonstrate marked influences of dietary carbohydrate and/or protein ingestion on oxidative biotransformation of drugs in man.

Adult↗
PubMed1976

The induction of heme oxidation in various tissues by trace metals: evidence for the catabolism of endogenous heme by hepatic heme oxygenase.

Cobalt is a potent inducer of hepatic heme oxygenase and concomitantly decreases microsomal cytochrome P-450 content in liver cells. Studies in which microsomal heme was labelled with 14C-beta-aminolevulinic acid showed that the decline observed in P-450 follows the induction of heme oxygenase indicating that endogenous heme is a substrate for this enzyme. The inducing effect of cobalt on heme oxygenase in liver extended to other organs such as heart, renal cortex and medulla, lungs and intestinal mucosa but not to the spleen and brain. In kidney and heart, cobalt resulted in decreases in microsomal and mitochondrial contents of hemoproteins. In addition ALAS activity of kidney was depressed by the metal. Other metals which chelate with sulfhydryl groups (e.g., Cr, Fe, Ni, Cu, Zn, Cd, Hg, Pb) were also shown to induce heart and renal heme oxygenase activities. Covalent binding of cobalt with mercaptans inactivated the metal with respect to its induction of heme oxygenase and degradation of hemoproteins.

Aminolevulinic Acid↗
PubMed1975

Studies in porphyria. IV. Expression of the gene defect of acute intermittent porphyria in cultured human skin fibroblasts and amniotic cells: prenatal diagnosis of the porphyric trait.

The gene lesion of the porphyrin-heme synthetic pathway in acute intermittent porphyria (AIP) is reflected in a deficient level of activity of the cytosol enzyme uroporphyrinogen I synthetase (URO-S). A marked URO-S deficiency has been demonstrated in the liver and in circulating erythrocytes of individuals with both active and latent AIP. This enzymic abnormality accounts for the excessive production and excretion into urine of the porphyrin precursors, lamda-aminolevulinic acid (ALA) and porphobilinogen (PBG) in AIP subjects. In this study, utilizing cell culture techniques, a marked URO-S deficiency has also been demonstrated in skin fibroblasts from AIP patients and in cells derived through aminocentesis from an approximately 17-wk old fetus. The prenatal diagnosis of the AIP trait in this fetus was confirmed postnatally by the demonstration in the child of a deficient level of erythrocyte URO-S activity which was comparable to those found in her AIP mother and affected sibling and which was approximately one-half the levels characterizing her normal father and aunt and a second unaffected sibling. The identification of the URO-S deficiency in cultured human fibroblasts from AIP patients was facilitated by a newly developed, sensitive assay for the enzyme activity. In this assay, the ability of such cells to convert ALA to protoporphyrin was quantitated; in the sequence of reactions involved in this transformation, URO-S is limiting so that the gene defect of AIP could be simply and precisely determined by appropriate spectrofluorometry of cell extracts. The technique described has distinct advantages over the direct enzymatic assay for URO-S activity in cultured human skin fibroblasts and permits clear differentiation of AIP carrier from normal individuals.

Abortion, Induced↗
PubMed1975

Cobalt stimulation of heme degradation in the liver. Dissociation of microsomal oxidation of heme from cytochrome P-450.

The administration of cobalt to rats caused a marked increase in the oxidative degradation of heme (hematin, iron protoporphyrin-IX) BY HEPATIC MICROSOMAL ENZYMES. The onset of this enzyme stimulation was very rapid, beginning within 2 hours after injection of the metal and reaching its maximum in 16 to 24 hours. During the rapid phase of stimulation, i.e. the first 2 to 4 hours, when heme oxidation was 450% above control values, there was a significant decrease in microsomal oxidative N-demethylation activity and in microsomal oxidative Ndemethylation activity and in microsomal content of heme with an insignificant decrease in cytochrome P-450 content. Within 24 hours the oxidative activity of the microsomal electron transport chain for drugs was decreased to about 30% of the control. However, during the same period the oxidation of heme approached levels 800% above control. During this period there was a further decrease in the microsomal content of heme with a significant decrease in cytochrome P-450 content and an increase in the activity of delta-aminolevulinate synthetase. The activity of delta-aminolevulinate synthetase reached its maximum within 8 hours after cobalt treatment. Repeated injections (at 24-hour intervals) of cobalt were necessary to maintain these changes in microsomal enzyme activities since, after single injections of the metal, these parameters returned to normal within 72 hours. The inducing effect of cobalt on the oxidation of heme could be inhibited by the administration of actinomycin D and puromycin. Furthermore, this stimulatory effect could not be elicited by in vitro treatment of microsomes with cobalt nor could the effect be attributed to any soluble components of the cytoplasm. Cobalt protoporphyrin-IX was less effective than cobalt chloride in stimulating heme oxidation. 3-Amino-1, 2, 4-triazole did not enhance hepatic heme oxidation activity, while allylisopropylacetamide decreased this activity. The oxidative degradation of heme was found not to be cytochrome P-450 dependent since the highly increased levels of heme oxidation in microsomes from cobalt-treated animals could be retained despite the fact that the cytochrome P-450 content of such microsomes was decreased to spectrally undetectable amounts and drug oxidation was eliminated by treatment of the microsomes with 4 M urea. These findings exclude an obligatory role for cytochrome P-450 in the oxidation of heme compounds, although the possibility that this process is a heme-dependent oxidation is not ruled out.

5-Aminolevulinate Synthetase↗
PubMed1975

Study of the developmental pattern of heme catabolism in liver and the effects of cobalt on cytochrome P-450 and the rate of heme oxidation during the neonatal period.

The comparative development patterns of heme oxidation andof cytochrome P-450 dependent drug oxidation in rat liver were examined. High levels of heme oxygenase activity were present in whole embryo preparations at day 13 of gestation. At birth this enzyme activity in liver was approximately equal to that of normal adult liver. In the immediate postnatal period the rate of hepatic heme oxidation increased sharply, reaching levels 3-5 times normal during the first week postpartum. Thereafter, this enzyme activity progressively decreased and returned to normal adult levels by the 28th postpartum day. The development of microsomal heme oxidation and of P-450 dependent drug oxidation exhibited reciprocal patterns, with the latter being at low levels of activity during the immediate postnatal period and reaching adult activity only 4 or more wk after birth. Cobalt injected into pregnant animals or in to nursing mothers did not induce heme oxygenase in the fetus or suckling neonate. However, when treated directly with the metal, 4-day old neonates exhibited a small induction response of this enzyme; and the inducibility of heme oxygenase increased gradually to fully adult levels by the end of the 4th postpartum week. Cobalt at all postnatal developmental stages was capable of diminishing hepatic contents of total microsomal heme and P-450; however this effect of the metal was small in the immediate period after birth and increased progressively with maturation. These findings demonstrate that the patterns of development of hepatic capacity for carrying out the oxidation of heme and the P-450 dependent oxidation of drugs are different and thus provide further evidence that these microsomal enzyme systems are distinct from each other and under separate regulatory mechanisms. The degree of induction response for hepatic heme oxygenase evoked by the trace metal, cobalt, was also shown to have developmental determinants as did the susceptibility of hepatic cytochrome P-450 to degradation by this metal. The very high levels of hepatic heme oxygenase activity which characterize neonates during the first week of life indicate that over-production of bilirubin contributes significantly to the mechanism of neonatal jaundice.

Animals↗
PubMed1975

The degradative effects of porphyrins and heme compounds on components of the microsomal mixed function oxidase system.

The effects of in vitro treatment of the hepatic microsomal fraction with various porphyrin compounds on the activity and the content of the heme-containing components of the mixed function oxidase system were studied. The compounds examined were hematin, methemalbumin (with heme to protein molar ratio of 13:1 or 1:1), mesohemalbumin, bilirubin, biliverdin, mesoporphyrin IX, and protoprophyrin IX. The activity of the system was monitored by measuring its oxidative activity for the type I and type II substrates, ethylmorphine and aniline, respectively; as well as the microsomal contents of cytochrome P-450 and b5 and 14C-labeled heme, Mesoporphyrin IX was found to be most effective in inhibiting the oxidative activity of the mixed function oxidase system as well as in decreasing the microsomal contents of cytochromes P-450, b5, and heme. Biliverdin exerted no effect on these parameters. Hematin and the other compounds studied exerted variable inhibitory effects on the system. The degradative and inhibitory effects of protoporphvrin IX and mesoporphyrin IS could be blocked significantly by conducting the studies in the dark. The presence of biliverdin decreased the inhibitory effects of the porphyrins on the system; conversely the effects could be magnified in the presence of deuterium oxide. It is suggested that the mechanism by which porphyrins inhibit the mixed function oxidase system is through porphyrin-sensitized photo-oxidation of various constituents of the hepatic microsomal fraction and that the formation of singlet oxygen molecules is most likely involved in this process. Moreover the destructive effects of heme compounds on the microsomal components and activities of the drug-metabolizing mixed function oxidase system raise questions concerning the hypothesis that the components of this system, and specifically cytochrome P-450, are involved in the activity of the heme oxygenase system.

Aminolevulinic Acid↗
PubMed1975

Drug metabolism in normal children, lead-poisoned children, and normal adults.

Drug-metabolizing capacities were determined in 10 normal adults and 10 children in the age range from 1 to 8 years. Among the latter, 2 were normal and 8 had biochemical evidence of lead poisoning but no clinical expression of plumbism. There were no differences between the 2 normal children and the 8 lead-poisoned children in their capacities to metabolize two test drugs, antipyrine and phenylbutazone. The mean antipyrine half-life in the whole group of 10 children, 6.63 hr, was significantly lower than the mean half-life of 13.58 obtained in adults. The mean phenylbutazone half-lives in the children and adults, 1.68 and 3.16 days, respectively, also differed significantly. Thus children in the age range studied appear to metabolize drugs at almost twice the rate of adults which differs from findings in animals in which drug-metabolizing capacities increase with maturation. In two other children who showed clinical as well as biochemical manifestations of acute plumbism, antipyrine half-lives were signficantly longer than normal and therapy with EDTA led to restitution toward normal.

Adult↗