Biomedical subjects

C Ioannides

Publications and source records attributed to C Ioannides.

At least 19 recordsLinked to original sources

PubMed1997

Diaminonaphthalenes and related aminocompounds: mutagenicity, CYP1A induction and interaction with the Ah receptor.

Using 1- and 2-aminonaphthalene as model substrates, we investigated the effect of insertion of a second amino group on mutagenicity, binding to the cytosolic Ah receptor and CYP1A inducibility, and the effects were compared to those elicited by 3,3'-diaminobenzidine and 1-naphthylethylenediamine. 1,5- and 1,8-diaminonaphthalene were effective inducers of CYP1A activity, more potent than 1-aminonaphthalene. 2,3-Diaminonaphthalene was also an inducer of CYP1A, but the effect was similar to that elicited by 2-aminonaphthalene. In contrast, 3,3'-diaminobenzidine and 1-naphthylethylenediamine did not induce CYP1A activity. All aminonaphthalenes displaced [3H]TCDD from the Ah receptor, whereas 3,3'-diaminobenzidine and 1-naphthylethylenediamine failed to do so. The latter two compounds did not elicit a mutagenic response in the Ames test. Introduction of a second amino group at the 3-position of 2-aminonaphthalene did not modulate its mutagenicity. In the case of the non-mutagenic 1-aminonaphthalene, introduction of a second amino group at position 5 had no effect but when it was incorporated at position 8, mutagenic potential was conferred to the molecule. Computer modelling of the putative active site of CYP1A2 revealed that 1,5-diaminonaphthalene is orientated so that the distance of the second amino group from the iron-oxene is 4.037 A while in the case of 1,8-diaminonaphthalene the distance is shorter, 2.744 A, favouring its activation through N-hydroxylation. Of the compounds studied, 1,8-diaminonaphthalene and, to a lesser extent, 2,3-diaminonaphthalene autoinduced their activation. It is concluded that insertion of a second amino group at the 5- or 8-position of 1-aminonaphthalene may enhance biological activity but in the case of 2-aminonaphthalene insertion of a second amino group at position 3 had no major effect.

1-Naphthylamine↗

PubMed1997

Reconstruction of extensive defects of the parotid region: experience with the pectoralis major and free latissimus dorsi flaps.

Large defects of the parotid region resulting from excision of malignant tumours, or necrotic tissue due to radiotherapy, should not always be closed with local tissue, for several reasons. Occasionally, myocutaneous flaps are indicated, giving better results. We describe the problems of such tissue defects and our experience over a 10-year period using 2 different flap reconstruction techniques. A total of 28 cases, 25 with malignant tumours of the parotid or the external ear, 2 with extensive radionecrosis of the parotid region and 1 with a burn, were evaluated. The defects were restored with a pectoralis major flap in 21 cases and with a free latissimus dorsi flap in 7 cases. The follow-up ranged from 18 to 60 months. The flaps were successful in achieving stable wound healing, restoration of tissue volume and in helping patients to return to normal life activities. There were complications in 28.5% of the cases. There were 2 early deaths due to encephalitis. Two pectoralis major flaps (9.5%) failed partially. All latissimus dorsi flaps survived. The pectoralis major proved to be useful, especially in older and medically compromised patients, whereas the latissimus dorsi fared well in younger female patients and in cases of a hemifacial resection defect. Numerous technical points in both methods are emphasized.

Adult↗

PubMed1996

Effect of vitamin C supplementation on hepatic cytochrome P450 mixed-function oxidase activity in streptozotocin-diabetic rats.

The effect of vitamin C supplementation on hepatic cytochrome P450 expression was investigated in streptozotocin (STZ) diabetic male Wistar Albino rats. STZ-treated rats displayed the usual characteristics of diabetes including; hyperphagia, polydipsia, decreased body weight gain and also the increased expression and activity of hepatic CYP1A, 2B, 2E and 4A proteins. Vitamin C administration in drinking water (2% w/v) was associated with significant decreases in the levels of hyperglycaemia (P < 0.05), glycosylated haemoglobin (P < 0.05), hyperlipidaemia (P < 0.001), and hyperketonaemia (P < 0.001) associated with STZ-diabetes. Vitamin C-treatment selectively reduced the activity and expression of CYP2E proteins (P < 0.001). These effects on CYP2E expression may be mediated by the reduced levels of circulating ketone bodies, however, a direct effect on CYP2E expression in diabetes cannot be discounted.

Animals↗

PubMed1996

Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: implications for their carcinogenicity.

The present study was undertaken to provide a rationale for the marked difference in carcinogenic potential among isomeric diaminotoluenes, in relation to their ability to induce their own bioactivation through CYP1A induction, their genotoxic potential, and their ability to bind to the cytosolic aromatic hydrocarbon (Ah) receptor. Of the four possible diaminotoluenes only the 2,3- and, to a lesser extent, the 2,4-isomer induced CYP1A activity. Similarly, only these two isomers could displace [3H]T-CDD from the hepatic cytosolic Ah receptor. In the presence of Aroclor 1254- induced microsomes, 2,4- and 2,6-diaminotoluene were potent mutagens in the Ames test. Only 2,4-diaminotoluene could autoinduce its activation. Of the four isomers only 2,4-diaminotoluene is an established carcinogen and this is compatible with the present observations that it is the only isomer that stimulates its own activation through CYP1A induction, is metabolically converted to genotoxic intermediates, and binds to the Ah receptor. 2,6-Diaminotoluene is recognized as a mutagenic noncarcinogen and in the present studies it elicited a positive mutagenic response in the Ames test but failed to induce CYP1A activity and its own activation, and could not bind to the Ah receptor even at concentrations as high as 5 x 10(-4) M. The present findings demonstrate that in vitro studies are very useful tools in predicting the carcinogenic potency of isomeric chemicals.

Animals↗

PubMed1996

Expression and inducibility of cytochrome P450 proteins in the liver of chick embryo.

The expression and inducibility of cytochrome P450 proteins in the liver of chick embryo were investigated using substrate probes and/or immunologically using polyclonal antibodies to the mammalian isoforms. Antibodies to CYP1A1 recognised a single protein which was inducible by structurally diverse chemicals, including aminocompounds, and was parallelled by increases in the O-dealkylations of ethoxy- and methoxyresorufin and in the bioactivation of Glu-P-1. When probed with antibodies to CYP2E1 an immunoreacting protein was revealed which was induced by phenobarbital but not acetone; a second protein became apparent following the treatment with phenobarbital. The increase in apoprotein levels was accompanied by similar increases in p-nitrophenol hydroxylase. Antibodies to CYP2C11 recognised two immunorelated proteins, of which one was inducible by phenobarbital. The same inducer, but not dexamethasone, enhanced the N-demethylation of erythromycin but antibodies to rat CYP3A1 failed to detect any proteins. Finally, lauric acid hydroxylation was not detectable in chick embryo and, moreover, no immunoreacting band was visible following probing of microsomes with anti-CYP4A1. It is concluded that proteins immunorelated to the mammalian CYP1 and CYP2 families are expressed in chick embryo but the regulation of the latter family in the embryo by exogenous chemicals differs markedly from that established for mammals.

Animals↗

PubMed1996

CT findings in osteoradionecrosis of the mandible.

CT scans of ten patients in whom the diagnosis of mandibular osteoradionecrosis was proven pathologically or by clinical follow-up were reviewed. All ten patients had bony abnormalities (cortical interruptions and loss of spongiosa trabeculation) on the symptomatic side. These were predominantly seen in the body of the mandible (premolar and molar region, eight patients), in some of these cases extending into the retromolar triangle (two patients) or mandibular angle (two patients). In the remaining two patients the abnormalities were in the ramus and angle. The two patients treated with iridium implantation showed localized lingual-sided cortical destruction. Three patients had a pathological fracture. The cortical destruction was buccal-sided in two and both buccal- and lingual-sided in three of the other five patients. Contralateral bony abnormalities were present in four patients. Soft tissue thickening on the symptomatic side was seen in nine patients. As the bony abnormalities in mandibular osteoradionecrosis are often associated with a soft tissue mass, CT differentiation from tumor recurrence can be difficult. The association with cortical defects distant from the position of the original tumor (buccal surface or opposite side of mandible) should evoke the possibility of mandibular osteoradionecrosis.

Adult↗

PubMed1996

Mutagenicity of white grape juice in the Ames test.

The mutagenicity of commercially available white grape juice was evaluated in the Ames mutagenicity test. Grape juice elicited a positive mutagenic, response in Salmonella typhimurium strain TA104 and a weaker response in strains TA97, TA98, TA100 and TA1530. The mutagenic response was evident in the absence of an activation system and inclusion of such a system did not influence mutagenicity. The grape juice-mediated mutagenic response was not due to histidine residues in the juice or likely treatment with sulfite. Moreover, freshly prepared grape juice displayed a similar mutagenic response. Three different brands of commercially available white grape juice were investigated in the Ames test; they all provoked a clear positive mutagenic response, but the degree of mutagenicity differed and could not be attributed to differences in the content of solids. It is concluded that grapes contain direct-acting genotoxic component(s).

Beverages↗

PubMed1996

Contribution of phenols, quinones and reactive oxygen species to the mutagenicity of white grape juice in the Ames test.

The purpose of this study was to evaluate the role of phenols, quinones and reactive oxygen species in the mutagenicity of white grape juice in the Ames mutagenicity test. Mutagenicity was markedly suppressed by reduced glutathione but was not influenced by superoxide dismutase or catalase. In the presence of grape polyphenol oxidase, the mutagenicity of grape juice was markedly increased. When hepatic cytosol from Aroclor 1254-induced rats, supplemented with a reduced nicotinamide adenine dinucleotide phosphate-generating system. served as an activation system, an increase in the mutagenicity of grape juice was observed. The cytosol-induced mutagenicity of grape juice was attenuated in the presence of superoxide dismutase, catalase and glutathione. It is concluded that polyphenol oxidase-catalysed oxidation of phenolic compounds generates genotoxic species that are, at least partly, responsible for the mutagenicity of grape juice. In the presence of hepatic cytosol, one-electron reduction of grape juice quinones leads to the production of reactive oxygen species resulting in an increase in the mutagenic response.

Animals↗

PubMed1996

A comparison of the antimutagenic potential of green, black and decaffeinated teas: contribution of flavanols to the antimutagenic effect.

The present study was undertaken to compare the antimutagenic activity of aqueous extracts, at the concentrations used for human consumption, from green, black and decaffeinated black tea. Antimutagenic potential was evaluated against three indirect-acting dietary carcinogens, Glu-P-1, benzo(a)pyrene and nitrosopyrrolidine. All three types of tea gave rise to strong and concentration-dependent suppression of the mutagenicity of the three premutagens in the presence of an activation system. No major difference in the antimutagenic potential of the three types of tea could be discerned. Black tea, decaffeinated black tea and, to a lesser extent, green tea also antagonized the mutagenicity of the direct-acting mutagen 9-aminoacridine. All three types of tea inhibited markedly the NADPH-dependent reduction of cytochrome c and the O-dealkylations of ethoxy-, methoxy- and, to a much lesser extent, pentoxy-resorufin. When the microsomal metabolism was terminated, after the metabolic activation of the premutagens, incorporation of the aqueous tea extracts into the activation system caused a concentration-dependent suppression of mutagenic response. No significant difference in the antimutagenic activity of the three types of tea in this system was evident. Bearing in mind the much higher concentration of flavanols in green tea compared with the black teas, it may be concluded either that these compounds are unlikely to be the major tea components responsible for the antimutagenic, and possibly anticarcinogenic, properties of tea or that their fermentation products are similarly active.

Aminacrine↗

PubMed1996

COMPACT and molecular structure in toxicity assessment: a prospective evaluation of 30 chemicals currently being tested for rodent carcinogenicity by the NCI/NTP.

A new series of 30 miscellaneous National Toxicology Program chemicals has been evaluated prospectively for carcinogenicity and overt toxicity by COMPACT (Computer Optimised Molecular Parametric Analysis for Chemical Toxicity. CYP1A and CYP2E1). Evaluations were also made by Hazardexpert, and for metal ion redox potentials; and these, together with COMPACT, were compared with results from the Ames test for mutagenicity in Salmonella, the micronucleus test, and 90-day subchronic rodent pathology. Seven of the 30 chemicals (nitromethane, chloroprene, xylenesulphonic acid, furfuryl alcohol, anthraquinone, emodin, cinnamaldehyde) were positive for potential carcinogenicity in the COMPACT evaluation; xylenesulphonic acid and furfuryl alcohol were only equivocally positive. Four of the 30 chemicals-scopolamine, D&C Yellow No. 11, citral, cinnamaldehyde-were positive by Hazardexpert; 6 of 30-D&C Yellow No. 11, 1-chloro-2-propanol, anthraquinone, emodin, sodium nitrite, cinnamaldehyde-were positive in the Ames test; 2 of 30-phenolphthalein and emodin-were positive in the in vivo cytogenetics test; and 3 of 30-molybdenum trioxide, gallium arsenide, vanadium pentoxide-were metal compounds with redox potentials of the metal/metal ion indicative of possible carcinogenicity. The overall prediction for carcinogenicity was positive for 12 of 30 chemicals: nitromethane, chloroprene, D&C Yellow No. 11, molybdenum trioxide, 1-chloro-2-propanol, furfuryl alcohol, gallium arsenide, anthraquinone, emodin, sodium nitrite, cinnamaldehyde, vanadium pentoxide). This overall prediction has been made on the basis of the results of the computer tests and from consideration of the information from bacterial mutagenicity, together with likely lipid solubility and pathways of metabolism and elimination.

Animals↗

PubMed1995

Defective expression of cytochrome P450 proteins in the liver of the genetically obese Zucker rat.

The hepatic expression of xenobiotic-metabolising cytochrome P450 isoforms in the genetically obese Zucker rat, a model of obesity, was compared to that of its lean littermate. Cytochrome P450 (CYP) levels were determined using diagnostic substrates and/or immunologically in Western blot analyses. When compared with the lean Zucker rat, the obese animal exhibited hyperglycaemia, hypercholesterolaemia, marked hyperinsulinaemia and hypertriglyceridaemia but was normoketonaemic. CYP3A and CYP1A2 levels were higher in the obese Zucker rat when compared with the lean littermate but, in contrast, a protein recognised by human CYP2D6 and, to a lesser extent, CYP2C11 levels were lower. Pretreatment with acetone, dexamethasone and clofibrate resulted in enhanced p-nitrophenol hydroxylase (CYP2E), erythromycin N-demethylase (CYP3A) and lauric acid hydroxylase (CYP4A) activities respectively in the liver of the lean Zucker rat but, in contrast, the obese Zucker rat was refractive to such treatment; similarly, hepatic apoprotein levels of the CYP2E and CYP4A subfamilies were increased markedly only in the lean Zucker rat. It is concluded that CYP2E, CYP3A and CYP4A subfamilies are poorly expressed in the obese Zucker rat, and this rat strain may serve as a good model for elucidating the molecular mechanisms of induction of these cytochrome P450 proteins.

Acetone↗

PubMed1995

Induction of hepatic CYP1A2 by the oral administration of caffeine to rats: lack of association with the Ah locus.

Caffeine was administered to male Wistar albino rats for two weeks at three concentrations, namely 0.1, 0.2 and 0.3%, and hepatic cytochrome P450-dependent mixed-function oxidase determined. Caffeine administration gave rise to a marked, dose-dependent increase in the O-deethylation of ethoxyresorufin and, to a lesser extent, in the O-depentylation of pentoxyresorufin. Erythromycin N-demethylase, p-nitrophenol hydroxylase and lauric acid hydroxylase activities, as well as total cytochrome P450 content were unaffected by this treatment. Immunoblot analysis revealed that caffeine gave rise to a dose-dependent increase in the hepatic CYP1A2, and at the highest dose only, CYP2B apoprotein levels. Apoprotein levels of CYP3A and CYP2E1 were not modulated by the treatment with caffeine at all dose levels studied. Caffeine could not displace [3H]TCDD from the rat hepatic cytosolic Ah receptor. Computer analysis showed that caffeine is essentially a planar molecule with an area/depth ratio 4.8, characteristic of CYP1A substrates/inducers. Molecular modelling revealed that the caffeine molecule could orientate itself within the putative CYP1A2 active site so as to facilitate demethylation of the N-1, N-3 and N-7 positions. However, at physiological pH, the N-9 nitrogen atom is likely to be partially protonated, allowing it to participate in an electrostatic interaction with the negatively-charged glutamate 318-residue, favouring N-3 demethylation, the major pathway of metabolism in both humans and animals. In conclusion caffeine, being essentially planar, is an inducer of CYP1A2 in rat liver.

Administration, Oral↗

PubMed1995

A quantitative structure-activity relationship study on a series of 10 para-substituted toluenes binding to cytochrome P4502B4 (CYP2B4), and their hydroxylation rates.

Molecular structural and molecular orbital calculations (AM1 method) are reported on a series of 10 para-substituted toluene derivatives and this structural information has been used to rationalize the differences between both rates of hydroxylation catalysed by cytochrome P4502B4 and binding to the same cytochrome P450, via the generation of quantitative structure-activity relationships (QSARs). It was found that the rate constant for hydroxylation can be described by a two-variable expression involving the dipole moment and volume of the solvent-accessible molecular surface (r = 0.98), whereas binding free energies are well characterized by combinations of molecular volume and various electronic frontier orbital parameters (r = 0.98 and 0.99). This study represents an advance on a previous evaluation by White and McCarthy (Arch Biochem Biophys 246: 19-32, 1986) who used empirical physico-chemical parameters to obtain similar results which were generally of lower statistical significance to those of the present work. The QSAR expressions suggest that both binding to P450 and metabolism for this series of compounds are dependent on the relative ability of the molecules to desolvate and occupy the heme binding site, together with electronic properties of the whole molecule and of the methyl group which undergoes hydroxylation.

Aryl Hydrocarbon Hydroxylases↗

PubMed1995

Expression and inducibility of cytochrome P450 proteins belonging to families 2,3 and 4 in the rabbit aorta.

The expression and inducibility of cytochrome P450 proteins belonging to families CYP2, CYP3 and CYP4 in the aorta of rabbits were investigated immunologically using polyclonal antibodies to the hepatic proteins. Antibodies to CYP2B recognised two proteins, only one of which was inducible by phenobarbitone. One protein was detected by anti-CYP2E1 which was modestly inducible by imidazole. A highly expressed protein was recognised by antibodies to CYP3A1, the levels of which diminished following treatment with rifampicin. Finally, antibodies to CYP4A1 immunoreacted with a single protein in the aorta which was refractive to treatment with ciprofibrate. The data demonstrate that the rabbit aorta expresses a number of cytochrome P450 families which, although inducible in the liver, are not always inducible in the aorta.

Animals↗

PubMed1995

CYP1 induction, binding to the hepatic aromatic hydrocarbon receptor and mutagenicity of a series of 11-alkoxy cyclopenta[a]phenanthren-17-ones: a structure activity relationship.

A series of four 11-alkoxy cyclopenta[a]phenanthren-17-ones, ranging from the methoxy to the butoxy derivative, has been synthesised in order to investigate the effect of the size of the 11-substituent on the mutagenicity and ability of these compounds to induce hepatic CYP1 activity in rats. The latter was monitored by using as diagnostic probes methoxy and ethoxy-resorufin, and immunologically in Western blots employing anti-CYP1A1 antibodies. All four members of the series induced both CYP1A1 and CYP1A2 activities and apoprotein levels, but the methoxy- and ethoxy-CPP-17-ones were clearly the most potent. Of the four isomers, only 11-methoxy-CPP-17-one displaced 3H-TCDD from the cytosolic Ah receptor. Similarly only 11-methoxy-CPP-17-one elicited a positive mutagenic response in the Ames test in the presence of an Aroclor 1254-induced activation system. The relevance of these findings to the carcinogenicity of these compounds in the mouse skin painting model is discussed.

Animals↗

PubMed1995

Stimulation of rat hepatic UDP-glucuronosyl transferase activity following treatment with green tea.

Studies were conducted to investigate whether aqueous extracts of green tea, administered to rats at concentrations consumed by humans, could influence the phase II conjugation reactions in the liver, and so contribute to its established anticarcinogenic activity. Exposure of rats to green tea (2.5%, w/v), as the sole drinking fluid, for 4 wk did not influence sulfotransferase, epoxide hydrolase nor glutathione S-transferase activities. UDP glucuronosyl transferase activity, when determined using 2-aminophenol as the substrate, was increased by 100% following treatment with tea. Finally, green tea had no effect on the enzymes affording protection against reactive oxygen species, namely catalase, glutathione peroxidase and superoxide dismutase. It is postulated that the enhanced glucuronidation may contribute to the anticarcinogenic effect of green tea by facilitating the metabolism of chemical carcinogens into inactive, readily excretable products.

Aminophenols↗

PubMed1995

The influence of dihydrodiol conformation on the metabolic activation of cyclopenta[a]phenanthrenes.

The present study was undertaken in order to rationalise the apparent biological inactivity of 15,16-dihydro-6-methylcyclopenta[a]phenanthren-17- one (4) when other methyl isomers of 15,16-dihydrocyclopenta[a]phenanthren- -17-one, e.g. the 11-methyl derivative (2), display appreciable tumorigenicity. In vitro metabolism of the 6-methyl-ketone-17-one (4) demonstrated that its principal metabolite was the 3,4-dihydro-3,4-diol (3,4-dihydroxy-6-methyl-3,4,15,16- tetrahydrocyclopenta[a]phenanthren-17-one) (5) which, in the case of the active 11-methyl derivative, is the proximate genotoxin. Thus the inactivity of this 6-methyl-17-ketone cannot be ascribed to lack of formation of the 3,4-dihydro-3,4-diol, the precursor of the 3,4-diol-1,2-epoxides (the ultimate mutagens in this series). However, the 6-methyl-3,4-dihydro-3,4-diol exists in a pseudo-diaxial rather than a pseudo-diequatorial conformation characteristic of the 3,4-dihydro-3,4-diols of the other members of the series. It is therefore suggested that a diequatorial conformation in the dihydrodiol is essential to the metabolic activation of the cyclopenta[a]phenanthren-17-ones.

Animals↗

PubMed1995

Computer graphics analysis of the interaction of alkoxy methylenedioxybenzenes with cytochromes P4501.

A quantitative structure-activity relationship (QSAR) in a homologous series of alkoxy methylenedioxybenzenes (MDBs) is reported. Measurements of molecular dimensions from computer-generated space-filling structures have provided values for the shape parameter area/depth2. These have been shown to correlate with the extent of inhibition of ethoxyresorufin O-deethylase activity by a series of MDBs. The implication of this is that the MDB nucleus fits the cytochrome P4501 substrate binding site and that this ability decreases with increase in the alkyl chain length of the alkoxy substituent. These findings are in agreement with previous results relating to the spatial dimensions of the cytochrome P4501 binding site, showing that substrate specificity can be rationalized in terms of overall molecular shape.

Animals↗