Search PubMed⌕ Search

Biomedical subjects

A Kappas

Publications and source records attributed to A Kappas.

At least 217 records · Page 12Linked to original sources
PubMed1981

Prevention of neonatal hyperbilirubinemia by tin protoporphyrin IX, a potent competitive inhibitor of heme oxidation.

The effects of various metalloporphyrins on hepatic heme oxygenase (EC 1.14.99.3) activity were examined in order to identify compounds that could inhibit heme degradation to bile pigment and might therefore be utilized to suppress the development of hyperbilirubinemia in the newborn. Among nine metal-protoporphyrin IX chelates (i.e., metal-hemes) studied, Sn-heme, Mn-heme, and Zn-heme substantially diminished heme oxygenase activity in vivo in the rat. These metalloporphyrins act as competitive inhibitory substrates in the heme oxygenase reaction but are not themselves oxidatively degraded. Sn-heme was the most potent enzyme inhibitor (Ki = 0.011 microM) in liver, spleen, kidney, and skin. Sn-heme administered to newborn animals within the first 72 hr after birth blocked the postnatal increase in heme oxygenase activity that occurs in various tissues. Its effect on the enzyme levels was prompt and protracted. Sn-heme administration also entirely prevented the development of hyperbilirubinemia that normally occurs postnatally. The effect of the metalloporphyrin in lowering the increased concentrations of serum bilirubin in neonates was prompt (within 1 day) and persisted throughout the 42 days after birth. No deleterious effects of Sn-heme treatment of the newborn were observed. This demonstrates that a synthetic metalloporphyrin that is a potent competitive inhibitor of heme oxidation can, when administered to the newborn, also prevent the hyperbilirubinemia that normally develops postnatally. The potential clinical implications of these findings are evident, and it is suggested that the pharmacological properties of Sn-heme and related synthetic metalloporphyrins merit further study.

5-Aminolevulinate Synthetase↗
PubMed1981

The potent heme oxygenase inducing action of arsenic and parasiticidal arsenicals.

The administration of trivalent arsenic, either as sodium arsenite or as the trypanocidal drug melarsoprol, to rats produced a profound induction of microsomal heme oxygenase (EC 1.14.99.3) in both liver and kidney and a concomitant decrease in cytochrome P-450 content. In addition, perturbations of delta-aminolevulinate synthase were observed which showed an initial decline followed by a rebound increase in the activity of this enzyme with arsenical treatment. Pentavalent arsenic did not induce hepatic heme oxygenase but did induce the enzyme in kidney, although to a lesser extent (50%) than trivalent arsenic. Treatment of isolated chick embryo liver cells in vitro with sodium arsenite or the parasiticidal drug melarsoprol also showed a potent induction of heme oxygenase. These findings describe a new and potent ability of arsenic and parasiticidal arsenicals to induce heme oxygenase resulting in enhanced degradation of cellular heme.

Animals↗
PubMed1981

[Operative treatment of the invasion of Echinococcus cysticus of the liver into the bile ducts].

The basic principles, methods, and results of treatment are reported from personal experience in the treatment of 32 patients with intrabiliary rupture of hydatid cysts of the liver. These patients were treated from 1970-1979 in Surgery I of the University of Thessaloniki. Total cystectomy combined with sphincteroplasty of the sphincter Oddi is the method of choice. The clinical data, special types of treatment, and indications are discussed. Reoperation during the same admission in some complicated cases is strongly recommended.

Adult↗
PubMed1980

Adrenalectomy enhances the induction of heme oxygenase and the degradation of cytochrome P-450 in liver.

The induction of hepatic heme oxygenase in response to cobaltous chloride (CoCl2) administration was examined in normal, sham-operated, and adrenalectomized rats. The basal level of heme oxygenase was elevated about 2-fold in adrenalectomized rats as compared to normal controls or sham-operated animals. The extent of heme oxygenase induction by CoCl2 was also increased about 2-fold above normal in adrenalectomized animals and was accompanied by an enhanced breakdown of cytochrome P-450. The initial decline (approximately 2 h) and the late rebound increase (approximately 16 h) of delta-aminolevulinate synthase activity caused by the metal administration were, however, similar for all three groups of animals. Hydrocortisone is known to restore the impaired inducibility of delta-aminolevulinate synthase by allylisopropylacetamide in adrenalectomized rats. In this study, treatment with hydrocortisone prevented the exaggerated metal induction of heme oxygenase but did not affect the associated initial decline or the late rebound of delta-aminolevulinate synthase. These data indicate that hydrocortisone and adrenalectomy can significantly influence the extent of the induction of heme oxygenase produced by CoCl2, but that both the initial decline and the rebound induction of delta-aminolevulinate synthase associated with this metal treatment are apparently independent of these endocrine controls.

5-Aminolevulinate Synthetase↗
PubMed1980

Metal ion interactions in the control of haem oxygenase induction in liver and kidney.

Mn2+ and Zn2+ exhibit a striking ability to block the induction by Sn2+ and Ni2+ of haem oxygenase (EC 1.14.99.3) in kidney. The blocking effects of Mn2+ and Zn2+ were found to be greatest on simultaneous administration, time-dependent when administered up to 8 h before the inducing metal ions, and ineffective when administered as little as 10 min after the inducing metal ions. The decreases in cytochrome P-450 and haem contents and the sequential changes in delta-aminolaevulinate synthase (EC 2.3.1.37) activity that occur concomitant with haem oxygenase induction were largely eliminated with simultaneous or prior treatment with Mn2+ or Zn2+, but not when Mn2+ or Zn2+ was administered after Sn2+ or Ni2+. Mn2+ and Zn2+ did not increase the catabolism of the enzyme in vivo. Zn2+ on simultaneous administration was also able substantially to block the induction of haem oxygenase by Co2+, Cd2+ and Ni2+ in liver. The Zn2+ blockade of Cd2+ induction was examined in detail, and prior or simultaneous administration of Zn2+ was found to be effective in blocking the induction of haem oxygenase and the concomitant decreases in cytochrome P-450 and haem contents, ethylmorphine demethylase activity and the sequential changes in delta-aminolaevulinate synthase activity. Zn2+ administration 10 min or more after Cd2+ was ineffective in preventing the occurrence of these perturbations in haem metabolism. These findings describe a new and striking biological property of Mn2+ and Zn2+, and indicate the existence of significant metal ion interactions in the control of haem metabolism.

5-Aminolevulinate Synthetase↗
PubMed1980

Prolonged induction of hepatic haem oxygenase and decreases in cytochrome P-450 content by organotin compounds.

The administration of organotin compounds to rats in single doses causes a significant and prolonged induction of haem oxygenase and a sustained decrease in haemoprotein content in the liver. The extent of induction of hepatic haem oxygenase varied between 3 and 5-fold at 72h after a single injection of water-insoluble organotins of differing structure. The alterations in haem metabolism produced by tricyclohexyltin hydroxide were studied in detail. The effects were dose-dependent, with doses as low as 3.75 mg/kg body wt. resulting in significant induction of haem oxygenase and a decrease in cytochrome P-450 and cytochrome b5 contents at 72h in the liver. The effects with time of a single dose of tricyclohexyltin on various parameters of liver haem metabolism were also examined. The organotin produced a substantial and very prolonged induction of haem oxygenase accompanied by a steady decline in cytochrome P-450 content for periods up to 8 days. The long duration of action of these organotins with respect to induction of haem oxygenase and depletion of cellular haemoprotein content provides a highly sensitive metabolic system with which to define further the toxic potential of organometals as well as to study the adaptive responses in liver to long-term perturbations of haem metabolism by foreign chemicals.

Animals↗
PubMed1980

Regulation of human drug metabolism by dietary factors.

Several dietary factors influence the oxidative metabolism of chemicals in humans. Increasing the ratio of protein to carbohydrate or fat in the diet, feeding cabbage and brussels sprouts or feeding charcoal-broiled beef for several days stimulates human drug metabolism. The chronic ingestion of ethanol stimulates drug metabolism whereas the chronic ingestion of methylxanthine-containing foods inhibits drug metabolism. In contrast, an increase in the ratio of fat to carbohydrate in the diet of normal subjects or the fasting of obese individuals for several days has little or no effect on drug metabolism. Flavonoids in edible plants influence the metabolism of foreign chemicals by human liver in vitro. The addition of flavone, tangeretin or nobiletin to human liver microsomes activates both the hydroxylation of benzo[alpha]pyrene and the metabolism of aflatoxin B1 to mutagens. On the other hand, quercetin, kaempferol, morin and chrysin, which are also normally occurring flavonoids, inhibit the hydroxylation of benzo[alpha]pyrene by human liver microsomes.

Adult↗
PubMed1980

Radiometric analysis of biological oxidations in man: sex differences in estradiol metabolism.

The oxidative metabolism of estradiol was studied in normal men and women by a radiometric procedure that provides information on the totality of the biotransformations concerned. The release of 3H into body water from estradiol labeled with 3H in the 17 alpha, 16 alpha, and C-2 positions permits measurement of the rate and extent of 17 beta-ol oxidation and of the competing hydroxylations at C-2 and 16 alpha, which lead to products with different biologicaly properties. In both men and women the 17 beta-ol oxidation is the most rapid transformation, followed by 2-hydroxylation and finally by 16 alpha-hydroxylation. Hydroxylation at C-2 predominates by a faccto of 2-4 over 16 alpha-hydroxylation. In men a large fraction (37%) of the substrate is unmetabolized at any of the three sites and is not excreted in urine; in women the corresponding fraction is only 18%. The estradiol fraction that does undergo metabolism is hydroxylated at C-2 vs. 16 alpha to a greater extent in women than in men. These major sex differences in the metabolism of estradiol in the human may have an important influence on the expression of the biological actions of the hormone. The radiometric technique used in this study can be generally applied to study the oxidative transformations of hormones, drugs, and other exogenous chemical that can be specifically labeled at reactive sites.

Aryl Hydrocarbon Hydroxylases↗
PubMed1980

Evaluation of operative choledochoscopy.

The accuracy of choledochoscopy in demonstrating calculi of the common bile duct has been assessed from 121 examinations with the rigid choledochoscope by 13 different surgeons. Choledochoscopy was used before an exploratory procedure in 48 patients and was without error in 45, but the procedure is not recommended because of the risks of unncessary choledochotomy. Postexploratory choledochoscopy was used in 73 patients. A correct diagnosis of the presence or absence of stones was provided in 64 patients, including unsuspected stones in 13. However, stones were missed in nine patients. When postexploratory T-tube cholangiography was combined with choledochoscopy, there were no diagnostic errors. It is concluded that, in all patients, after choledochotomy, choledochoscopy should be combined with cholangiography.

Cefazolin↗
PubMed1979

Steroid induction of delta-aminolevulinic acid synthase and porphyrins in liver. Structure-activity studies and the permissive effects of hormones on the induction process.

Quantitative aspects and structure-activity relationships of the inducing effects of natural steroids on delta-aminolevulinic acid (ALA) synthase and porphyrins have been investigated in monolayer cultures of chick embryo liver cells maintained in a serum-free medium as well as in the chick embryo liver in ovo. Many 5 alpha and 5 beta metabolites of neutral C-19 and C-21 hormones and hormone precursors stimulated porphyrin formation and ALA-synthase induction in the cultured liver cells as we have previously described. In these inducing actions a number of 5 beta epimers (A:B cis) were found to be more potent than their corresponding 5 alpha epimers (A:B trans). The structure-activity relationship between 5 beta and 5 alpha steroid epimers with respect to ALA-synthase induction in culture was also found to prevail with respect to induction of this enzyme in chick embryo liver in ovo. Hemin in concentrations of 2 x 10(-7) M inhibited steroid induction of porphyrin formation, and CaMgEDTA enhanced the responsiveness of the cultured liver cells to steroids by approximately 10 times. The addition of insulin, or insulin plus hydrocortisone or insulin plus hydrocortisone plus triiodothyronine, was important for the maintenance of protein synthesis and essential for maximal expression of the ability of steroids to induce porphyrins and ALA-synthase in the "permissive" effect which insulin, hydrocortisone, and triiodothyronine exert on allylisopropylacetamide induction of porphyrins and ALA-synthase also extends to the induction process which is elicited by natural steroids. These findings also strongly suggest that the regulation of hepatic porphyrin-heme biosynthesis by endogenous as well as exogenous chemicals is significantly influenced by the internal hormonal milieu.

5-Aminolevulinate Synthetase↗
PubMed1979

The influence of steroid hormone metabolites on the in vitro development of erythroid colonies derived from human bone marrow.

Certain C19 and C21 steroid metabolites, when incubated with normal human bone marrow cells in culture, increased the number of erythroid colonies in the presence of erythropoietin. Among a number of pairs of C5 epimeric steroids tested, most 5beta (A:B cis) steroids stimulated the growth of both early erythroid progenitor cells (BFU-E) and late erythroid progenitor cells (CFU-E), whereas only a few 5alpha-(A:B trans) steroids stimulated the growth of CFU-E. No 5alpha-compounds of six pairs of steroids studied were found to stimulate BFU-E formation. This structure-activity relationship conforms with that previously observed in studies of steroid induction of ALA-synthase in avian embryo liver cells and hemoglobin synthesis in the cultured avian blastoderm. When human bone marrow cells were preincubated with the steroids for 2 d, followed by incubation with erythropoietin, only the 5 beta-compounds stimulated the growth of BFU-E. Similarly, when addition of steroids was delayed in relation to erythropoietin in the culture, only the 5 beta-derivative of a pair of C5 epimeric compounds displayed an enhancing effect on the growth of BFU-E. This effect required that the steroid addition be made no later than 48 h after initiation of the culture. These data demonstrate that certain natural steroid metabolites significantly stimulate erythropoiesis in normal human bone marrow cells in culture. They also indicate that 5 beta-compounds are more stimulatory than their 5 alpha-epimers, and they suggest that these 5 beta-steroids act preferentially on very primitive erythroid progenitor cells, probably on BFU-E.

Androstanes↗
PubMed1979

Operative choledochoscopy.

We have reported the results of 121 examinations with the rigid choledochoscope performed by 13 different surgeons between 1969 and 1977. Pre-exploratory choledochoscopy was performed in 48 patients with a diagnostic accuracy of 94 per cent. Post-exploratory choledochoscopy was used in 73 patients to define whether the common bile duct had been adequately cleared of stones. Fifty-one patients were correctly assessed as having a clear duct and unsuspected residual calculi were demonstrated by choledochoscopy in 13 patients. However, choledochoscopy failed to identify 9 patients with retained stones. The accuracy of post-exploratory choledochoscopy alone was 87 per cent and the accuracy of post-exploratory cholangiography was 82 per cent, but when choledochoscopy was combined with post-exploratory cholangiography there were no errors. We conclude that the addition of choledochoscopy to conventional radiological techniques is likely to reduce the incidence of residual calculi after choledochotomy.

Cholangiography↗
PubMed1979

Intraindividual variation in drug disposition.

Large interindividual differences occur in the in vivo metabolism of drugs due to genetic and environmental factors. Our studies show that intraindividual variabilities in rates of metabolism are relatively low for antipyrine and phenylbutazone, which are drugs that are primarily metabolized by the liver and have low hepatic extractions; whereas in the case of phenacetin, a drug that undergoes extensive metabolism in the gastrointestinal tract or during its first pass through the liver, or both, intraindividual variations in plasma half-lifes and areas under the plasma concentration-time curves are of much greater magnitude. In our studies, no effort was made to control the lifestyles of our subjects. The variations in rates of drug metabolism did not result from assay procedures, since there was little variation in measured concentrations when the drugs were added to plasma and assayed on multiple occasions. Intraindividual variation occurring in subjects given the drug on 5 different occasions may be due to changes in the external environment or changes in internal physiologic parameters or both. Our studies confirm the usefulness of antipyrine as a test drug in studying drug metabolism in man and also demonstrate that the antipyrine test may be able to detect those subjects whose environments are perturbed by unidentified factors.

Administration, Oral↗