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Biomedical subjects

C Ioannides

Publications and source records attributed to C Ioannides.

At least 199 records · Page 11Linked to original sources
PubMed1984

Active metabolites in toxicology: the role of cytochrome P-448 and flavoprotein oxidases.

The activation of toxic chemicals and carcinogens into reactive intermediates involves oxygenation in hindered positions of the molecule, by cytochrome P-448 (LM4), flavoprotein oxidoreductases, or transoxygenation during prostaglandin biosynthesis. Cytochrome P-450 (LM2) does not oxygenate in hindered positions and therefore generally detoxicates carcinogens and toxic chemicals. Cytochrome P-448 has a different active site from cytochrome P-450, which enables it to oxygenate substrates in conformationally-hindered positions.

Animals↗
PubMed1984

Inhibition of rat hepatic mixed function oxidases by antimalarial drugs: selectivity for cytochromes P-450 and P-448.

Intraperitoneal administration of chloroquine, primaquine and quinacrine to rats resulted in inhibition of the hepatic microsomal mixed-function oxidases. The N-demethylation of benzphetamine (cytochrome P-450) was inhibited by chloroquine only while the O-deethylation of ethoxyresorufin (cytochrome P-448) was inhibited by primaquine and quinacrine. When incubated with hepatic microsomes from phenobarbital-pretreated rats, chloroquine and primaquine, but not quinacrine, caused a concentration-dependent inhibition of benzphetamine N-demethylase activity. Incubation of hepatic microsomes from beta-naphthoflavone rats with primaquine and quinacrine, but not chloroquine, resulted in a concentration-dependent inhibition of the O-deethylation of ethoxyresorufin. These observations demonstrate that chloroquine and quinacrine are specific inhibitors of cytochromes P-450 and P-448, respectively.

Animals↗
PubMed1984

Trauma of the upper third of the face. Management and follow-up.

Of 407 patients with facial fractures who were operated on at the Department of Oral and Maxillo-Facial Surgery, University Hospital, Nijmegen, over a 3-year period, 23 had a fracture in the nasofrontal region with or without extension to the base of the skull. The problems and results of the treatment of these fractures are presented, with special reference to the management of the frontal sinus lesions, the lacrimal system, and the reconstruction of the nasal skeleton and canthal attachments. The postoperative complications and sequellae are discussed. Most prominent features are ocular problems and unsatisfactory nasal contour. Conclusions which could contribute to the proper therapeutic management are drawn.

Adolescent↗
PubMed1984

A comparative study of the bioactivation of nitrosamines to mutagens by various animal species including man.

Dimethylnitrosamine, dipropylnitrosamine, methylethylnitrosamine, nitrosopiperidine and nitrosopyrrolidine were assayed for mutagenicity in the Ames test in the presence of hepatic postmitochondrial preparations isolated from the mouse, rat, hamster, pig and man. Prior to each mutagenicity assay all activation systems were fully characterised with respect to monoamine oxidase, mixed-function amine oxidase and mixed-function oxidase activities. The hamster was the most efficient activator for all nitrosamines followed by the mouse. The latter species, however, activated nitrosopyrrolidine only weakly which was the only carcinogen readily activated by the human preparation. None of the aliphatic nitrosamines was activated by the rat or pig. No correlation was observed between efficiency of activation and any of the enzyme activities studied.

Animals↗
PubMed1984

Polyadenylic acid polymerase activity in normal and leukemic human leukocytes.

Soluble polyadenylic acid [poly(A)] polymerase and poly(A) nucleases content of normal human blood lymphocytes and leukemic blood cell populations was determined. Blood lymphocytes from seven normal individuals were used as controls. Leukemic cells were obtained from 69 patients with various types of acute and chronic leukemias. Chronic lymphocytic leukemias presented poly(A) polymerase values with a mean of 9 +/- 4 (S.D.). Although most of the chronic lymphocytic leukemia cases presented poly(A) polymerase activities similar to those of normal lymphocytes (3 +/- 3), a small number fell into the specific activity values of acute leukemias, which were significantly higher and covered a wider range. The mean values for acute myeloblastic, acute monoblastic, and acute lymphoblastic leukemias were 53 +/- 50, 21 +/- 8, and 29 +/- 14, respectively. A statistically significant difference was found between chronic and acute leukemias (p less than 0.01). The observed differences in poly(A) polymerase levels of acute lymphoblastic leukemia versus chronic lymphocytic leukemia persisted after fractionation of the crude extracts and, furthermore, they could not be attributed to differences in the levels of poly(A)-degrading enzymes [poly(A) endo- and exonucleases]. Fractionation of leukemic extracts on Sephadex G-75 revealed two molecular forms of poly(A) polymerase activity.

Humans↗
PubMed1983

Effect of deuteration of imipramine on its pharmacokinetic properties in the rat.

Imipramine was specifically deuterated in either both aromatic rings or in the N-methyl group, or in both positions, and the pharmacokinetic properties of the products were determined in the rat and compared with those of the non-deuterated analogue. Deuteration of imipramine resulted in a small but significant isotope effect on N-demethylation while aromatic hydroxylation was unaffected. This isotope effect led to a slower rate of systemic clearance, a longer half-life and, when orally administered, enhanced bioavailability. Urinary excretion of didesmethylimipramine-d4, following oral administration of imipramine-d7, was significantly lower than the excretion of didesmethylimipramine following administration of unlabelled imipramine, indicating inhibited demethylation. Similarly, the urinary excretion of desmethylimipramine-d4, didesmethylimipramine-d4 and 2-hydroxydesmethylimipramine-d4 were lower than for the corresponding unlabelled or d7-analogues, indicating the stability of the N-CD3 group. Deuteration had no effect on the pharmacological properties of imipramine as determined in this study.

Animals↗
PubMed1983

Activation of aromatic amines to mutagens by various animal species including man.

2-Acetylaminofluorene, 2-aminofluorene, 4-aminobiphenyl, 2-naphthylamine, 2-aminoanthracene and benzidine were assayed for mutagenicity in the Ames test in the presence of hepatic microsomal preparations derived from mouse, hamster, rat, pig and man. Prior to each mutagenicity assay all activation systems were fully characterized with respect to mono-oxygenase and mixed-function amine oxidase activities. All compounds were metabolically activated to mutagens by all activation systems, but with markedly different efficiencies, hamster being the only species which readily activated all amines. The hamster also exhibited the highest ethoxyresorufin O-deethylase and dimethylaniline N-oxidase activities.

2-Acetylaminofluorene↗
PubMed1983

Acute toxicity of 3-deoxy-4-sulphohexosulose in rats and mice, and in vitro mutagenicity in the Ames test.

3-Deoxy-4-sulphohexosulose (DSH) is formed in sulphited foods by the interaction of SO2 and intermediates of the Maillard reaction. The acute intragastric toxicity of DSH has been studied in rats and mice, and the LD50 was found to exceed 5 g/kg body weight in both species. The only adverse effect seen in a 14-day post-dosing period was a transient diarrhoea in the first 24 hr. DSH was shown to be non-mutagenic in four strains of Salmonella typhimurium in the Ames test, with and without metabolic activation by S-9 mix from Aroclor-treated rats.

Animals↗
PubMed1983

A comparison of the protective effects of N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity.

The protective effect of the sulphur-containing amino acids N-acetyl-cysteine and S-carboxymethylcysteine against paracetamol-induced hepatotoxicity was evaluated in the hamster by biochemical and histological methods. Of the animals receiving paracetamol alone 25% died within 24 h following administration. All surviving animals showed acute hepatocellular injury and marked loss of cytochrome P-450 and hepatic mixed-function oxidase activities. Simultaneous administration of N-acetylcysteine decreased the mortality rate, partly prevented the paracetamol-induced liver damage and partly restored enzyme activities. Simultaneous administration of S-carboxymethylcysteine with paracetamol afforded no protection. Kidneys from all animals were histologically normal. Human liver microsomes and liver microsomes from 3-methylcholanthrene-pretreated hamsters metabolished paracetamol to intermediate(s) that bind covalently to microsomal proteins. The rate of covalent binding was inhibited markedly by N-acetylcysteine and to a lesser extent by S-carboxylmethylcysteine.

Acetaminophen↗
PubMed1983

Species variation in the metabolic activation of paracetamol to toxic intermediates: role of cytochromes p-450 and p-448.

The metabolic activation of paracetamol to reactive intermediate(s) covalently bound to microsomes was investigated using microsomal preparations from various laboratory animals and man. The hamster and mouse, in contrast to the rat, were good activators. Microsomal preparations from 3-methylcholanthrene (3MC)-induced hamsters were markedly more efficient in activating paracetamol than similar preparations from phenobarbital (PB)-induced animals. The activation of paracetamol by the 3MC-induced hamster preparations was inhibited by 9-hydroxyellipticine but not by metyrapone. These results indicate that hepatic cytochrome P-448 but not cytochrome P-450 can convert paracetamol to reactive intermediate(s) which bind covalently to microsomal proteins.

Acetaminophen↗
PubMed1983

The role of highly purified forms of rat liver cytochrome P-450 in the dimethylation of dimethylnitrosamine and its activation to mutagens.

Highly purified NADPH-cytochrome P-450 reductase and the major phenobarbital (PB) and beta-naphthoflavone (beta NF) forms of cytochrome P-450 were used in reconstituted systems to study the demethylation and subsequent activation of dimethylnitrosamine (DMN) to mutagenic intermediates. Both forms of cytochrome P-450 were active in the demethylation of DMN, cytochrome P-450 from PB-treated animals being more efficient, generating nearly twice as much formaldehyde per nmol of haemoprotein. Neither form of the cytochrome could activate DMN to mutagens in the Ames test. These findings indicate that DMN demethylation does not lead to its activation to mutagenic products.

Animals↗
PubMed1983

Effect of some beta-adrenergic blocking agents on tissue guanylate cyclase and cyclic nucleotides in the rat.

Pretreatment of rats with the beta-adrenergic blocking agents, atenolol, practolol, pronethalol and propranolol, at a dosage of 150 mg/kg/day for 5 days, produced marked increases in guanylate cyclase activity in the liver, gastric and intestinal mucosae, but with concomitant decreases in cyclic GMP levels. The ratios of cAMP/cGMP in each of the tissues were not changed significantly from control values after pretreatment with these drugs. These observations indicate that any oncogenicity seen with beta-blocking agents is not due to the common pharmacological action of beta-adrenoreceptor blockade.

Adrenergic beta-Antagonists↗
PubMed1983

Studies on the possible mutagenicity of beta-adrenergic blocker drugs.

The mutagenic potential of nine beta-adrenergic blocking agents was investigated in the Ames and micronucleus tests. None of the drugs studied showed any mutagenic response in the Ames test, either in the presence or in the absence of an activation system. At the highest concentration oxprenolol and propranolol exhibited a bactericidal effect. In the micronucleus test the same drugs showed a weak, but statistically non-significant response, but only at the highest doses. It is concluded that there is no overt mutagenic or carcinogenic potential associated with beta-adrenergic blocking drug activity.

Adrenergic beta-Antagonists↗
PubMed1983

Apicoectomy on molars: a clinical and radiographical study.

Apicoectomies on molars are not performed frequently, although their success rate can reach that obtained by apicoectomies on front teeth and premolars. 86 patients were operated on between January 1976 and December 1980 at St. Radboud Hospital. Clinical and radiological re-examination could be carried out on 70 of them. In 73% of the cases, healing was complete, in 21% incomplete, and in 6% the teeth were extracted. Certain factors which possibly influenced healing and the methods of root filling are discussed.

Adolescent↗
PubMed1983

The role of highly purified cytochrome P-450 isozymes in the activation of 4-aminobiphenyl to mutagenic products in the Ames test.

The role of cytochromes P-450 and P-447 in the activation of 4-aminobiphenyl to mutagens in the Ames test was studied using S9 preparations and highly purified isozymes. S9 preparations from beta-naphthoflavone-pretreated rats were more efficient in converting 4-aminobiphenyl to mutagens than the corresponding preparations from phenobarbitone-pretreated animals. Similarly, reconstituted systems comprising purified cytochrome P-447 were twice as efficient as cytochrome P-450 in activating the carcinogen. Of all the known Phase I metabolites of 4-aminobiphenyl, only the N-hydroxy-derivative was mutagenic in the Ames test. These findings indicate that arylamine N-hydroxylase is a cytochrome P-450 dependent enzyme, and the nature of the isozyme of the cytochrome is an important determinant of its mutagenicity.

Aminobiphenyl Compounds↗
PubMed1983

Metabolic activation of paracetamol by highly purified forms of cytochrome P-450.

The metabolic activation of paracetamol (acetaminophen) to reactive intermediate(s) which bind covalently to proteins was studied in reconstituted systems, employing highly purified preparations of cytochromes P-450 and P-448 isolated from the liver of rats pretreated with phenobarbitone and beta-naphthoflavone respectively. Cytochrome P-448 readily catalysed the activation of paracetamol, but in contrast no activation was observed when cytochrome P-450 was used at the same concentration. Addition of purified epoxide hydratase to the incubation system had no effect on the extent of covalent binding to proteins, indicating that an arene oxide is unlikely to be the reactive intermediate responsible for the paracetamol-induced hepatotoxicity.

Acetaminophen↗
PubMed1982

Impairment of absorption of ascorbic acid following ingestion of aspirin in guinea pigs.

A study was undertaken to investigate the interactions between aspirin and ascorbic acid in guinea pigs. Animals received by gastric intubation either a single dose of radiolabelled ascorbic acid alone or ascorbic acid with aspirin and the exhalation of CO2 was monitored for 400 min following administration. Animals receiving the vitamin only reached plasma peak levels within 90 min following administration while coadministration of the vitamin with aspirin, not only resulted in lower plasma peak levels, but also delayed their attainment until after 160 min. The bioavailability of ascorbic acid during the first 400 min was reduced by half following simultaneous administration of aspirin. The initial rate of exhalation of CO2 was decreased by 70% following coadministration of aspirin. These observations indicate that aspirin impairs the gastrointestinal absorption of ascorbic acid in guinea pigs, possibly by interfering with its active transport.

Animals↗