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Biomedical subjects

C Ioannides

Publications and source records attributed to C Ioannides.

At least 217 records · Page 12Linked to original sources
PubMed1982

Studies on the substrate-binding sites of liver microsomal cytochrome P-448.

The interaction of substrates of the microsomal mixed-function oxidases with cytochromes P-450 and P-448 was investigated by using liver microsomes from rats pretreated with phenobarbital or 3-methylcholanthrene, and with purified forms of the cytochromes isolated from rabbit liver. The two forms of the cytochrome have different substrate specificities; cytochrome P-450 has one type 1 substrate-binding site that can accommodate a large variety of substrates, but in contrast cytochrome P-448 may possess two type 1 substrate-binding sites, one of which is different to that of cytochrome P-450 in that it shows a specificity for substrates such as safrole and 9-hydroxy-ellipticine. These findings explain why the two forms of the cytochrome have different substrate specificities and play contrasting roles in the activation and deactivation of xenobiotics.

Animals↗
PubMed1982

Inhibition of gastrointestinal mucosal glycoprotein synthesis by the beta-adrenergic blocking drug, practolol.

The effect of administration of practolol and other beta-blocking agents on gastrointestinal mucosal glycoprotein synthesis was studied in the rat. Practolol, at a dose of 50 mg/kg, inhibited the incorporation of N-acetylglycosamine into gastric mucosal glycoproteins, while acebutolol, atenolol, pronethalol and propranolol had no inhibitory effect, even at a dose of 200 mg/kg. In addition, practolol inhibited the incorporation of N-acetylneuraminic acid, D-fucose and L-serine into gastric mucosal glycoproteins, while the other beta-blocking agents had no effect. Administration of practolol caused no significant change in the rate of incorporation of glycoprotein precursors into intestinal mucosal glycoproteins. These results indicate that of the beta-blocking drugs studied, inhibition of glycoprotein synthesis is associated only with practolol and is independent of its beta-blocking effect.

Adrenergic beta-Antagonists↗
PubMed1982

Selective inhibition of the safrole-induced mixed-function oxidase activities by 9-hydroxyellipticine.

Intraperitoneal administration of 9-hydroxyellipticine, a specific cytochrome P-448 inhibitor, inhibited 3-methylcholanthrene-induced cytochrome P-448 activity (ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase) and formation of the safrole carbene ligand complex with this cytochrome, but did not inhibit phenobarbital-induced cytochrome P-450 activity (ethyl-morphine N-demethylase) or formation of the safrole carbene ligand complex with this cytochrome. Biphenyl displaced the 9-hydroxyellipticine ligand from cytochrome P-448 leading to increased free cytochrome, but with no corresponding increase in mixed-function oxidase activity when biphenyl was used as substrate. It is concluded that following dissociation of the ligand complex, 9-hydroxyellipticine, which also exhibits type I binding, competes with biphenyl for the substrate binding site. Administration of 9-hydroxyellipticine to safrole-pretreated rats inhibited the cytochrome P-448-catalysed activity, but had no effect on the cytochrome P-450-catalysed activity. These results indicate that safrole induces a mixture of cytochromes P-450 and P-448 rather than a single novel haemo-protein. The type I substrate biphenyl displaced both the safrole carbene and the 9-hydroxyellipticine ligands from cytochrome P-448 resulting in increased free cytochrome. Displacement of the safrole carbene ligand was accompanied by increased mixed-function oxidase activity but, in contrast, displacement of the 9-hydroxyellipticine ligand resulted in no increase in mixed-function oxidase activity.

Alkaloids↗
PubMed1982

Metabolic activation of dimethylnitrosamine to mutagens: role of cytochromes P-450 and P-448.

Pretreatment of hamsters with phenobarbitone, 3-methylcholanthrene and Arochlor 1254 induced the hepatic microsomal mixed function oxidases, yet decrease the efficiency of activation of dimethylnitrosamine (DMN) to intermediates mutagenic to the Salmonella typhimurium strain TA-100. Furthermore, no correlation was obtained between cytochrome P-450 content, microsomal demethylation of DMN and its activation to mutagens. These results indicate that the demethylation of DMN by the mixed-function oxidases is not the rate-limiting step in the metabolic activation of the carcinogen to mutagen(s), and that other microsomal or soluble enzymes may be involved.

Animals↗
PubMed1982

The mutagenicity of 9-hydroxyellipticine and its induction of cytochrome P-448 activity in rat liver microsomes.

Administration of a single dose of the inhibitor of the hepatic mixed function oxidases, 9-hydroxyellipticine (9-OHE), resulted in a marked increase in the cytochrome P-448 catalysed activities of ethoxyresorufin O-deethylase, biphenyl 2-hydroxylase and activation of benzo[a]pyrene to mutagens. In contrast there was no effect on the cytochrome P-450 catalysed benzphetamine N-demethylase activity. The inductive effect was prevented by simultaneous administration of the protein synthesis inhibitors cycloheximide and actinomycin D. It is concluded that 9-OHE may also act as an inducer of the hepatic microsomal mixed function oxidases, selectively inducing the synthesis of cytochrome P-448. Therefore, 9-OHE, like other inhibitors of this enzyme system, exhibits a biphasic effect, its inhibitory phase being followed by one of enzyme induction. 9-OHE was a direct mutagen in the Salmonella typhimurium strains TA 98 and TA 100.

Alkaloids↗
PubMed1982

Elimination of glyceryl trinitrate: effects of sex, age, species and route of administration.

1 Orally administered glyceryl trinitrate to rats undergoes extensive first pass metabolism leading to low bioavailability. 2 Sex differences in the plasma elimination of glyceryl trinitrate were seen in the rat, the female exhibiting the longer plasma half-life. No sex differences in this respect were detected in the rabbit. 3 The plasma half-life of glyceryl trinitrate was longer and the volume of distribution larger, in older animals. 4 The plasma elimination of glyceryl trinitrate was different in various animal species. There was a good correlation between plasma half-life and animal bodyweight.

Aging↗
PubMed1981

Activation of benzo(a)pyrene and 2-acetamidofluorene to mutagens by microsomal preparations from different animal species: role of cytochrome P-450 and P-448.

1. The metabolic activation of benzo(a)pyrene and 2-acetamidofluorene to mutagens was studied with liver microsomal preparations from rat, guinea-pig, hamster and mouse, untreated or pretreated with phenobarbitone or 3-methylcholanthrene. 2. Liver microsomal preparations from all animal species activated benzo(a)pyrene, that from mouse being the most efficient. Similarly, microsomal preparations from guinea-pig, hamster and mouse could activate 2-acetamidofluorene, but that from rat exhibited very weak activity. 3. Activation of benzo(a)pyrene into mutagenic intermediates by liver microsomal preparations was increased for all animals except mouse by pretreatment with 3-methylcholanthrene. In contrast, pretreatment with phenobarbitone decreased the activation by microsomal preparations from all species. 4. Activation of 2-acetamidofluorene by liver microsomal preparations from rat and guinea-pig, but not mouse and hamster, was increased by pretreatment of the animals with phenobarbitone. Pretreatment with 3-methylcholanthrene decreased the activation of this carcinogen by microsomal preparations from all species. 5. The metabolic activation of benzo(a)pyrene is catalysed by cytochrome P-448 but not cytochrome P-450. 6. The activation of 2-acetamidofluorene to mutagens may involve, in addition to the mixed-function oxidases, other microsomal enzyme systems.

2-Acetylaminofluorene↗
PubMed1980

Ligand binding of safrole to cytochrome P-450.

Safrole, a hepatocarcinogen, is converted by the microsomal mono-oxygenase system to a reactive intermediate which interacts with cytochrome P-450 to form a ligand complex. The formation of this complex is accompanied by loss of mono-oxygenase activity. The present study describes the interaction of the safrole reactive intermediate with microsomes from phenobarbital, 3-methylcholanthrene and safrole pretreated animals.

Animals↗
PubMed1980

Inhibition of cytochrome P-448 mixed function oxidase activity following administration of 9-hydroxyellipticine to rats.

The in vitro inhibitor of mixed-function oxidation, 9-hydroxyellipticine, non-competitively inhibited the binding of the type II substrate, aniline, to cytochrome P-448 of hepatic microsomal preparations from rats pretreated with 3-methylcholanthrene. In contrast, 9-hydroxyellipticine did not inhibit the binding of aniline to cytochrome P-450 of hepatic microsomal preparations from rats pretreated with phenobarbitone, nor did it inhibit the binding of the type I substrate, hexobarbitone to either cytochrome P-450 or cytochrome P-448. Following the pretreatment of rats intraperitoneally with 9-hydroxyellipticine and phenobarbitone, the cytochrome P-448-specific enzyme activity, ethoxyresorufin O-deethylase, was 50% inhibited in vitro but cytochrome P-450, cytochrome P-450 reductase, and other mixed function oxidase activities were unaffected. With rats pretreated with 9-hydroxyellipticine and 3-methylcholanthrene, inhibition of ethoxyresorufin O-deethylase was 90%, and cytochrome P-450/P-448, cytochrome P-450 reductase, biphenyl 2- and 4-hydroxylase were inhibited by 30, 15, 50 and 40% respectively. It is concluded that 9-hydroxyellipticine administered in vivo markedly inhibits mixed-function oxidations which are specific to cytochrome P-448, but has no effect on cytochrome P-450-catalysed microsomal oxidation.

Alkaloids↗
PubMed1979

Effect of diet on the metabolism and toxicology of drugs.

The human organism is continuously exposed to a variety of xenobiotics, as drugs, pesticides, food additives and many environmental contaminants, all of which are potentially toxic. The body metabolizes these highly reactive chemicals to pharmacologically-inert compounds, which are readily eliminated from the body. This process of deactivation is dependent on nutritional status. Malnutrition, almost invariably, leads to a reduced capacity to deactivate these exogenous materials with consequent increase in toxicity.

Animals↗