Enhancement of 2-hydroxylation in vitro of biphenyl by organochlorine insecticides [proceedings].
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Animals↗
Biomedical subjects
C Ioannides
Publications and source records attributed to C Ioannides.
The effect of allyl compounds on hepatic microsomal mixed function oxidation and porphyrogenesis.
The activities of 5-aminolaevulinate (5-ALA) synthetase and of various microsomat drug-metabolising enzymes have been determined in the livers of rats pretreated with different drugs and chemicals containing the allyl group. Safrole, isosafrole and secobarbital gave rise to slight increases in 5-ALA synthetase, whereas alclophenac and triallyl cyanurate almost doubled the enzyme activity and the known porphyrogenic agents, allylisopropylacetamide (AIA) and allobarbital caused increases of 1.5- and 2.5-fold, respectively. Allobarbital induced the microsomal drug-metabolising enzymes while secobarbital had only a weak effect and alclophenac and triallyl cyanurate had no effect at all. From these results it is suggested that induction of the synthesis of cytochrome P-450 is not rate dependent on the synthesis haem and induction of porphyrin biosynthesis.
5-Aminolevulinate Synthetase↗
Mechanism of induction of hepatic microsomal drug metabolizing enzymes by a series of barbiturates.
The inducing effect of certain barbiturates (secobarbitone, thiopentone, pentobarbitone, allobarbitone, phenobarbitone and barbitone) on the levels of the hepatic microsomal drug-metabolizing enzymes has been studied in the rat both in vivo and in vitro. The extent of induction was related to the plasma half-lives of the barbiturates; compounds with low rates of metabolism and long half-lives were the most potent inducing agents. The latter (phenobarbitone, pentobarbitone and allobarbitone) were shown by spectral technique to interact with cytochrome P-450 suggesting that their mechanism of enzyme induction was 'substrate induction' in type. Barbiturates containing an allyl group (secobarbitone and allobarbitone) had a weaker inducing effect than expected, possibly due to their destruction of cytochrome P-450. Despite its short plasma half-life of 0-5 h thiopentone was a relatively potent inducer probably due to its metabolism to pentobarbitone, which has a much longer plasma half-life (1-3 h). Barbitone is an effective inducer of the drug-metabolizing enzymes, yet does not interact spectrally with cytochrome P-450; this is in accord with the observations that although there are increases in NADPH-cytochrome c reductase and cytochrome b5, following administration of barbitone there is no increase in cytochrome P-450. Barbiturate pretreatment does not affect the activities of glucose-6-phosphatase, glucose-6-phosphate dehydrogenase or 6-phosphogluconate dehydrogenase.
Animals↗
Enhancement of hepatic microsomal drug metabolism in vitro following ethanol administration.
1. Administration of ethanol intraperitoneally at low dosages (10-25 mg/kg) to rats stimulates hepatic microsomal mixed-function oxidase activity in vitro. 2. Pretreatment with ethanol administered orally has no effect on in vivo drug metabolism as measured by pentobarbitone plasma half-life and has no effect on the excretion of ascorbic acid. Ethanol administration does not enhance its own binding to cytochrome P-450. 3. These observations suggest that the administration of ethanol, at moderate dosage, does not give rise to induction of hepatic cytochrome P-450. 4. Unwashed hepatic microsomes are contaminated with alcohol dehydrogenase, but pretreatment with ethanol does not increase microsomal generation of NADH. 5. Pretreatment with ethanol has no stimulatory effect on NADH-NADP+ transhydrogenation. 6. The stimulation of hepatic drug metabolism in vitro following administration of ethanol is not due to increased cytochrome P-450 nor to increased NADPH, per se, but appears to result from an increase in the activity of NADPH-cytochrome c reductase.
Animals↗
Serratus anterior muscle in composite head and neck flaps.
The serratus muscle (SAM) can be raised as an isolated muscular or osteomuscular flap on its nutrient vessels or in combination with a latissimus dorsi (LD) myocutaneous flap on the thoracodorsal pedicle for various reconstructive purposes. The aim of the present is to report on the results achieved after the use of the SAM alone (n = 7) and in combination with an LD (n = 3) after tumor resection or osteoradionecrosis (ORN) in ten patients with defects of the head and neck. One flap was lost due to venous thrombosis. The donor site morbidity was minimal. Emphasis is given on a new indication, namely ORN of the mandible. Short-term results show that the use of the SAM prevents a pathologic fracture in cases of a class IIIa osteoradionecrotic mandible. More extensive use of the SAM flap is advocated.
Adult↗
The use of computers in the safety evaluation of drugs and other chemicals.
The toxicity and carcinogenicity of drugs and other chemicals is, in most cases, mediated by highly reactive intermediates which are generated following metabolism catalysed by the enzymic apparatus of the exposed organisms. These reactive intermediates readily interact covalently with vital cellular components to provoke toxicity and carcinogenicity. The ubiquitous cytochrome P450-dependent mixed-function oxidases are the most important enzyme system in the activation of chemicals. This enzyme system comprises a number of families, each of which contains one or more subfamilies. The CYPIA and CYP2E subfamilies are the most closely associated with the production of reactive intermediates and, consequently, the manifestation of toxicity and carcinogenicity. A computer based molecular structure procedure (COMPACT) has been developed which, via a calculation of the molecular and electronic structure of the chemical, determines whether the chemical will interact with either of these two cytochrome P450 subfamilies and hence be metabolised to form reactive intermediates that manifest toxicity. As the basal levels of these two subfamilies are generally low, the ability of a chemical to induce them selectively, on repeated administration, is an important determinant of its toxic and carcinogenic potential. This inductive capability may be determined in short-term studies (ENACT) using only a small number of animals. Thus the combination of COMPACT and ENACT provides a rapid and inexpensive means for the preliminary screening of chemicals for toxicity and carcinogenicity before undertaking the long-term and expensive rodent lifetime bioassays.
Animals↗
Anthraflavic acid inhibits the mutagenicity of the food mutagen IQ: mechanism of action.
The ability of anthraflavic acid to inhibit the mutagenicity of IQ was investigated using the Ames test and employing hepatic activation systems from Aroclor 1254-pretreated rats. Incorporation of anthraflavic acid into the S9 mix caused a concentration-dependent decrease in the mutagenicity of IQ. A similar effect was seen when microsomes only were employed as activation systems. Cytosol, as we have previously demonstrated, potentiated the microsome-mediated mutagenicity of IQ and this potentiation was also inhibited by anthraflavic acid. In contrast, anthraflavic acid had no effect on the mutagenicity of the direct-acting microsome-generated metabolites of IQ. It is concluded that anthraflavic acid is a potent inhibitor of IQ mutagenicity by virtue of its ability to inhibit both its microsomal and cytosolic activation pathways.
Animals↗
Induction of rat hepatic cytochrome P-450 I proteins by the antimutagen anthraflavic acid.
Administration of the antimutagen anthraflavic acid to rats gave rise to significant increases in the hepatic microsomal O-deethylations of ethoxyresorufin and ethoxycoumarin, but not in the O-dealkylation of pentoxyresorufin nor in cytosolic glutathione S-transferase activity. Immunoblot studies of solubilized microsomes from anthraflavic acid-treated rats revealed that anthraflavic acid induced the apoproteins P-450 I A1 and A2 but not P-450 B1 and B2. Pretreatment with anthraflavic acid resulted in a marked increase in the in vitro bioactivation of 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-amino-3,2-amino-3-methylimidazomethylimidazo[4,5-f]-quinoline (IQ) to mutagenic intermediate(s); IQ is a carcinogen against which anthraflavic acid has displayed strong antimutagenic effect in the Ames test when incorporated into the metabolic activation system. The increase in mutagenicity of IQ was the result of enhancement of both the microsomal and cytosolic activation steps. It is concluded that anthraflavic acid is a specific inducer of P-450 I proteins in the rat and this compound is not only unlikely to exhibit any anticarcinogenic effect in vivo but may act as a co-carcinogen.
Animals↗
Induction of the P-450 I family of proteins by polycyclic aromatic hydrocarbons: possible relationship to their carcinogenicity.
The hypothesis has been put forward that mutagenic polycyclic aromatic hydrocarbons which induce the P-450 I family of cytochromes, the major enzyme system responsible for their activation, are likely to be carcinogenic. In order to test this hypothesis, rats have been pretreated with a number of polycyclic aromatic hydrocarbons of different mutagenic and carcinogenic potency and hepatic P-450 I activity was monitored using chemical probes such as the O-deethylation of ethoxyresorufin and metabolic activation of Glu-P-1 to mutagens, and immunologically employing polyclonal antibodies against purified rat P-450 I A1. All compounds studied enhanced P-450 I activity and induced P-450 I apoproteins but the extent of induction was very markedly different. The results are discussed with reference to the mutagenicity of these chemicals in the Ames test and their carcinogenicity in the classical mouse skin model. A relationship appears to exist between carcinogenicity of polycyclic aromatic hydrocarbons and their ability to induce hepatic P-450 I activity.
Animals↗
The mutagenic and cell transforming properties of shikimic acid and some of its bacterial and mammalian metabolites.
Known and proposed metabolites of shikimic acid were synthesised, characterised and tested for genotoxic activity using the Salmonella/mammalian microsome mutagenicity test, the bacterial fluctuation mutagenicity test and the BHK 21 cell transformation test. Under the conditions used, none of these compounds showed any activity. However, shikimic acid itself was active in the BHK 21 cell transformation assay. It therefore seems unlikely that shikimic acid is a carcinogenic initiating agent, but it may act as a carcinogen-promoting agent in the bracken fern (Pteridium aquilinum).
Animals↗
Fractures of the frontal sinus: classification and its implications for surgical treatment.
PURPOSE: To propose a clinical classification of fractures of the frontal sinus and discuss the implications on treatment. PATIENTS AND METHODS: One hundred patients with fractures of the frontal sinus seen and operated on in two University hospital units (Leuven and Nijmegen). The majority of the patients were surgically treated according to a protocol based on the proposed classification. Fractures were classified according to their location, extent, involvement of the nasofrontal duct, and injury to the dura. Fragments were reduced and fixed, defects were reconstructed with autologous bone grafts, and the sinus cavity was drained, obliterated, or cranialized. In the latter cases, the sinus mucosa was thoroughly removed before obliteration or cranialization. RESULTS: The follow-up ranged from 6 months to 12 years. There were functional complications in 4% of patients. Minor aesthetic sequelae were noticed in 14% of the patients. CONCLUSION: A detailed classification of fractures of the frontal sinus is proposed. It has helped the authors set up a treatment protocol. Optimally, if used by clinicians, it will contribute to a more standardized method of surgical care of patients with such injuries.
Adolescent↗
The mutagenicity and interactions of 2- and 4-(acetylamino)fluorene with cytochrome P450 and the aromatic hydrocarbon receptor may explain the difference in their carcinogenic potency.
A study has been undertaken to identify the properties of 2-(acetylamino)fluorene which render it carcinogenic, in contrast to the 4-isomer, the carcinogenic potential of which is, at best, very weak. Compared to the 4-isomer, 2-(acetylamino)fluorene was a more potent inducer of cytochrome P450 1A (P450 1A) activity, as exemplified by the O-deethylation of ethoxyresorufin (P450 1A1), the metabolic activation of Glu-P-1 (P450 1A2), and immunoblot analysis. These findings were consistent with the relative affinity of these compounds for the cytosolic aromatic hydrocarbon receptor, determined by the displacement of tetrachlorodibenzo-p-dioxin. In the presence of Aroclor 1254-induced hepatic microsomal and cytosolic preparations 2-(acetylamino)-fluorene elicited a potent mutagenic response in the Ames test whereas the 4-isomer, in both cases, elicited a weak mutagenic response. Molecular orbital calculations of the relative energetics of the nitrenium ions revealed that the ion of the 2-isomer was more stable than the nitrenium ion of 4-(acetylamino)fluorene. Control hepatic microsomal and cytosolic fractions could activate 2-(acetylamino)fluorene to mutagens in the Ames test. Pretreatment of animals with 2-(acetylamino)fluorene enhanced both the microsome- and cytosol-mediated activation. In contrast, microsomal and cytosolic fractions from control animals could not activate 4-(acetylamino)fluorene, but following pretreatment with the compound itself, a weak mutagenic response in the presence of microsomes, but not of cytosol, was evident.(ABSTRACT TRUNCATED AT 250 WORDS)
2-Acetylaminofluorene↗
The evaluation in the Ames test of the mutagenicity of tetrahydro-beta-carboline-3-carboxylic acids from smoked foods.
This paper reports the evaluation of five tetrahydro-beta-carboline carboxylic acids, formed from the interaction of woodsmoke carbonyls and tryptophan, for mutagenicity in the Ames test. Three of the compounds tested have been detected recently in smoked foods at levels in the micrograms/kg or mg/kg range. None of the compounds induced mutagenicity in TA 97, TA 98 or TA 100 strains of Salmonella typhimurium either with or without prior activation. However, tetrahydro-beta-carboline-3-carboxylic acid, and to a lesser extent 1-methyl-tetrahydro-beta-carboline-3-carboxylic acid were toxic to the strains of Salmonella typhimurium used. The inability of these beta-carbolines to induce mutation contrasts markedly with the mutagenicity of some beta-carbolines found in grilled meat products.
Carbolines↗
Quantitative structure-activity relationships and COMPACT analysis of a series of food mutagens.
Quantitative structure-activity relationships between chemical structure and Ames mutagenicity for a group of 24 food mutagens, including 17 cooked-food heterocyclic amines, have been determined. For the TA98 strain of Salmonella typhimurium (frameshift mutagens) the best correlation of mutagenicity is with molecular diameter (R = 0.91), while for the TA100 strain (base-pair mutations) the best correlation is with delta E, the energy difference between the lowest unoccupied and highest occupied molecular orbitals. High mutagenicity is related to high values of molecular diameter, hence to planarity and to high values of the COMPACT ratio ([area/depth2]/delta E). High mutagenicity is also related to low values of delta E. Consequently, highly mutagenic and potentially carcinogenic food chemicals can readily be identified as substrates of cytochrome P4501 (CYP1) and may therefore be detected by the COMPACT procedure. Highly mutagenic compounds also exhibit high values of dipole moment.
Carcinogens↗
Cytochrome P-448 and the activation of toxic chemicals and carcinogens.
The metabolic activation of carcinogens and some toxic chemicals appears to involve oxygenation in conformationally hindered positions in the chemical molecules. Oxygenation of xenobiotics in hindered positions is effected by cytochrome P-448 (LM4) but not by cytochrome P-450 (LM2). Substrate-interaction spectra show that cytochrome P-448 has an active site with a conformation different from that of cytochrome P-450. Induction of cytochrome P-448, as specifically measured by ethoxyresorufin O-deethylase activity, occurs in rat liver, kidney and lung after administration of the carcinogens, 3-methylcholanthrene, Aroclor 1254, 2-anthramine, safrole, 7,12-dimethylbenz[a]anthracene, MNNG and 2-acetamidofluorene. The doubtful carcinogens, saccharin, DDT and aldrin, resulted in no significant induction. The drugs paracetamol, antipyrine, imipramine and rifampicin resulted in diminished enzyme activity, indicating the absence of any induction of cytochrome P-448. In studies with the matched pairs of carcinogens and non-carcinogens, benzo[a]pyrene and benzo[e]pyrene, and 1,2,5,6-dibenzanthracene and anthracene, only the carcinogenic analogue resulted in induction of cytochrome P-448. With alpha- and beta-naphthylamine, both resulted in marked induction of cytochrome P-448 in liver, kidney and lung, indicating that both isomers might be carcinogenic.
Animals↗
[Pectoralis major myocutaneous island flap for cervicofacial reconstruction: a 9-year experience].
The Pectoralis major island flap for cervico-facial reconstructions: a nine year experience. The pectoralis major m.c. flap was used for the restoration of post-tumorectomy defects in 220 patients (n = 224). 181 flaps were used for internal and 43 for external reconstructions. The overall failure rate was 9% (2.7% partial failures and 6.4% total failures). The causes which led to partial or total necrosis of a flap are analyzed. The results are compared to those of the literature. It is concluded that the above mentioned is a versatile flap in cervico-facial reconstructive surgery with a high success rate provided certain basic principles are respected during dissection and during the early postoperative period.
Adult↗
[Large dermoid cyst of the floor of the mouth: report of a case].
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Child↗
The metabolic activation of 2-naphthylamine to mutagens in the Ames test.
The mutagenicity of 2-naphthylamine and its major metabolites in the Ames test was determined in the absence and presence of activation systems derived from rats and hamsters. In the absence of an activation system only N-hydroxy-2-naphthylamine and 2-nitrosonaphthalene were mutagenic. In the presence of activation systems derived from control and 3-methylcholanthrene-treated hamsters and Arochlor 1254-treated rats only 2-naphthylamine exhibited a mutagenic response while its hydroxy-derivatives and 2-acetamidonaphthalene were devoid of mutagenicity. Pretreatment of rats with 3-methylcholanthrene or Arochlor 1254 enhanced the mutagenicity of 2-naphthylamine while treatments with phenobarbitone, safrole and clofibrate had no significant effect. In the hamster treatment with only 3-methylcholanthrene increased the mutagenicity of 2-naphthylamine. It is concluded that the metabolic activation of 2-naphthylamine proceeds via N-hydroxylation which is preferentially catalysed by the 3-methylcholanthrene inducible forms of cytochrome P-450, whereas ring-hydroxylation appears to be a deactivation pathway.
2-Naphthylamine↗