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Biomedical subjects

A Kappas

Publications and source records attributed to A Kappas.

At least 325 records · Page 18Linked to original sources
PubMed1972

Studies in porphyria. I. A defect in the reductive transformation of natural steroid hormones in the hereditary liver disease, acute intermittent porphyria.

A variety of 5beta steroid metabolites derived from hormones natural to man are potent inducers experimentally of delta-aminolevulinate synthetase, the rate-limiting enzyme in porphyrin-heme formation. This mitochondrial enzyme is found at high levels of activity in the livers of patients with the genetic disease, acute intermittent porphyria (AIP). In this study the metabolism of (14)C-labeled testosterone was examined in AIP patients to determine whether there was a disproportionate conversion of the hormone to its 5beta, compared to its 5alpha metabolite. The results indicate that AIP subjects do generate a substantially greater than normal fraction of 5beta metabolite from this steroid; the excessive degree of ring A reduction of testosterone taking place via the 5beta pathway in the porphyric patients averages 350% greater than in the nonporphyric subjects. In one asymptomatic AIP patient the disproportionate generation of 5beta metabolite from the hormone reached a level 10 times the normal mean. Studies with a second (14)C-labeled hormone, dehydroisoandrosterone, whose metabolism in man resembles that of testosterone, confirmed the derangement in reductive transformation of steroids found in the individuals carrying the genetic lesion of AIP. These findings define a new endocrine abnormality in AIP patients and raise the possibility that endogenously derived 5beta steroids may contribute by an induction mechanism to the increased levels of hepatic delta-aminolevulinate synthetase activity found in AIP patients.

5-Aminolevulinate Synthetase↗
PubMed1972

Lead and methyl mercury: effects of acute exposure on cytochrome P-450 and the mixed function oxidase system in the liver.

The rat liver mixed function oxidase system which is responsible for the metabolism of endogenous and exogenous compounds has been shown to be affected by lead and methyl mercury. Administration of these environmental pollutants to rats results in a decrease in cytochrome P-450 content and inhibition of in vitro N-demethylase and hydroxylase activities. The in vitro enzyme-inhibiting effects of the metals found pharmacological expression in the whole animal by prolongation of hexobarbital-induced sleeping times.

Aniline Compounds↗
PubMed1972

Induction of benzo( )pyrene hydroxylase in human skin.

Foreskins from children who were circumcised 2 to 4 days after birth contain an enzyme system that hydroxylates the carcinogen benzo[alpha]pyrene. When foreskin was cultured for 16 hours in the presence of 10 micromolar benz[alpha]anthracene, a two- to fivefold increase in activity of benzo[alpha]pyrene hydroxylase was obtained. An evaluation of the basal activity and inducibility of carcinogen-metabolizing enzymes in human tissues may provide a means of determining the ability of different individuals to metabolize carcinogens.

Benz(a)Anthracenes↗
PubMed1972

Assays for porphyrins, delta-aminolevulinic-acid dehydratase, and porphyrinogen synthetase in microliter samples of whole blood: applications to metabolic defects involving the heme pathway.

Three micromethods are described for the assay of enzymes or products of the heme biosynthetic pathway in blood. A fluorometric method for the assay of protoporphyrin may be applied to the rapid screening of children for chronic lead poisoning. A colorimetric assay for delta-aminolevulinic-acid dehydratase may be applied to the detection of acute and chronic lead poisoning. A fluorometric assay for porphyrin formation from prophobilinogen is also described.

Acute Disease↗
PubMed1972

Coproporphyrin I and 3 excretion in bile and urine.

The excretion of coproporphyrin isomers I and III was studied in the rat. Both isomers were found to bind equally to rat plasma and liver cytosol in vitro and to disappear from plasma at equal rates after single injections in vivo. During equimolar infusions of isomers into bile fistula animals, both the I and III isomers were excreted in bile in a concentration ratio of 2:1, respectively. Pretreatment of animals with ethinylestradiol or simultaneous infusions of phenoldibromophthalein disulfonate caused a reduction in total hepatic excretion with no change in the 2:1 ratio in bile. As hepatic excretion fell, excretion of both isomers in urine rose, with an increase in the proportion of the I isomer. The findings mimic those reported to occur in man and can be explained by inhibition of a common carrier which requires a stereospecific configuration that statistically favors the hepatic transport of the symmetrical coproporphyrin I isomer.

Animals↗
PubMed1971

The influence of postnatal development on drug-induced hepatic porphyria and the synthesis of cytochrome P-450. A biochemical and morphological study.

The mitochondrial enzyme delta-aminolevulinate synthetase (ALAS) controls the rate-limiting step in the synthesis of porphyrins and heme. An experimental form of hepatic porphyria can be readily elicited in laboratory animals, such as the rat, by drugs and foreign chemicals which are known to enhance the de novo formation of this enzyme in the liver. The present study shows that there is a striking refractoriness to the induction of ALAS during the perinatal period in the rat. Chemicals which have potent porphyria-inducing activity in adult animals have no significant inducing effect on hepatic ALAS in neonates. The ultrastructural changes which accompany the induction of ALAS by drugs and chemicals in adult liver also fail to take place in the livers of neonates. A progressive capacity for responding to the action of chemical inducers of hepatic ALAS does, however, develop in neonatal animals so that by approximately 5-6 wk of age experimental porphyria can be elicited as effectively in them as in adults. The reasons for the refractoriness of hepatic ALAS to induction in the perinatal period are not known; but the findings of this study make it clear that ALAS belongs to that increasingly large group of liver enzymes in mammals whose appearance, increase of activity, or inducibility is developmentally determined. The occurrence of developmental changes in the indicibility of ALAS in the liver of neonates also provided an opportunity to study the relationship of this enzyme activity to the drug-mediated induction of the hepatic hemoprotein cytochrome P-450. This inducible hemoprotein serves as the terminal oxygenase in the microsomal mixed-function oxidase system in the liver. The results of this study indicate that, in contrast to the refractoriness of ALAS to induction, significant drug-induced changes of hepatic P-450 content and of hemeprecursor incorporation into this cytochrome do take place in neonates. The synthesis of P-450 thus appears to be under a regulatory control different from that of ALAS in neonates, and the relation between ALAS activity and P-450 formation is not therefore a direct one.

Acyltransferases↗
PubMed1971

Isolation and biochemical characterization of nuclei from chick embryo liver.

A procedure is described for the isolation of enzymatically active nuclei from chick embryo liver. It consists of the homogenization of the pooled tissue in 0.32 M sucrose-3 mM MgCl(2) followed by a slow centrifugation. The resulting nuclear pellet is then purified further in a discontinuous density gradient composed of sucrose solutions containing Mg(2+) ions, the lower portion of the gradient being 2.2 M sucrose-1 mM MgCl(2). Based on DNA recovery, the nuclear fraction isolated by the procedure described contained an average of 62% of the nuclei in the original filtered homogenate. Light and electron microscope examinations showed that 90% of the isolated nuclei were derived from hepatocytes. They appeared intact with well preserved nucleoplasmic and nucleolar components, nuclear envelope, and pores. The isolated nuclei were quite pure, having a very low level of cytoplasmic contamination as indicated by cytoplasmic enzyme marker activities and electron microscope studies. The nuclear fraction consisted of 19.9% DNA, 6.2% RNA, 74% protein, the average RNA/DNA ratio being 0.32. Biosynthetic activities of the two nuclear enzymes NAD-pyrophosphorylase and DNA-dependent RNA polymerase were preserved. The specific activities of these enzymes were: NAD-pyrophosphorylase, 0.049 micromoles nicotinamide adenine dinucleotide (NAD) synthesized/min per mg protein; Mg(2+) activated RNA polymerase, 4.3 micromicromoles UMP-2-C(14) incorporated into RNA/microg DNA per 10 min; and Mn(2+)-(NH(4))(2)SO(4) activated RNA-polymerase, 136 micromicromoles UMP-2-C(14) incorporated into RNA/microg DNA per 45 min.

Animals↗