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Biomedical subjects

D F Lewis

Publications and source records attributed to D F Lewis.

At least 109 records · Page 6Linked to original sources
PubMed1994

Induction of hepatic microsomal CYP4A activity and of peroxisomal beta-oxidation by two non-steroidal anti-inflammatory drugs.

The effects of the non-steroidal anti-inflammatory drugs fenbufen and ibuprofen on hepatic cytochrome P450 activities and peroxisomal proliferation were investigated in the rat, following intraperitoneal administration at three dose levels. At the two highest doses, 30 and 150 mg/kg, ibuprofen stimulated lauric acid hydroxylase activity but no other dose-dependent effects on cytochrome P450 activities were evident. Fenbufen, at the highest dose of 150 mg/kg, decreased cytochrome P450 content and related activities, and this effect was attributed to the toxicity of the drug at this dose. Immunoblot studies employing solubilized microsomes from ibuprofen-treated rats revealed that ibuprofen increased the apoprotein levels of CYP4A1, at the two higher doses. The same treatment with ibuprofen, at the highest dose only, increased the beta-oxidation of palmitoyl CoA, determined in liver homogenates, and immunoblott analysis showed an increase in the apoprotein levels of the trans-2-enoyl CoA hydratase trifunctional protein. Fenbufen did not influence palmitoyl beta-oxidation. Computer graphic overlays with clofibric acid showed that ibuprofen, when compared with fenbufen, displayed a better overall fit to clofibric acid. Finally, interaction energies between the two drugs and the putative peroxisome proliferator-activated receptor ligand domain revealed that ibuprofen had a higher affinity for the receptor than fenbufen, but the difference was modest. It is concluded that ibuprofen, at doses far exceeding those employed clinically, is a weak inducer of both CYP4A1 activity and peroxisomal proliferation and these effects may be attributed to the presence of an aryl propionic acid moiety.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Studies on the acute effects of coumarin and some coumarin derivatives in the rat.

The mechanism of acute coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl-substituted coumarin derivatives. Male Sprague-Dawley rats were given single ip doses of corn oil (control), coumarin (0.86 and 1.71 mmol/kg body weight), 3,4-dimethylcoumarin (3,4-DMC, 1.71 and 2.57 mmol/kg), 3-, 4- and 6-methylcoumarins (3-MC, 4-MC and 6-MC, 1.71 mmol/kg) and 3- and 4-methyloctahydrocoumarins (3-MOHC and 4-MOHC, 2.57 mmol/kg) and hepatotoxicity assessed after 24 hr. Coumarin administration produced dose-related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, none of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Treatment with coumarin reduced hepatic microsomal ethylmorphine N-demethylase and 7-ethoxycoumarin O-deethylase activities, whereas one or both mixed-function oxidases appeared to be induced by treatment with 3,4-DMC, 4-MC, 3-MOHC and 4-MOHC. These results provide further evidence that acute coumarin-induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. That 3- and/or 4-methyl substitution (i.e. 3-MC, 4-MC and 3,4-DMC) leads to a reduction in coumarin-induced hepatotoxicity, due to diminished formation of 3,4-epoxide intermediates, was confirmed by the results of molecular orbital calculations.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1994

Safety evaluations of food chemicals by "COMPACT". 1. A study of some acyclic terpenes.

A group of 19 acyclic terpenes have been evaluated for potential toxicity/carcinogenicity by molecular orbital determinations of their spatial and electronic parameters, and hence prediction of their metabolic activation or detoxication by the cytochrome P-450 (CYP) superfamily of mixed-function oxidase enzymes. Previous studies have characterized the spatial dimensions of the CYP1A1, 1A2 and 2E1 enzymes, which are known to activate mutagens and carcinogens and to be involved in other mechanisms of toxicity. None of the terpenes was found to have shape or electronic parameters appropriate for metabolic activation by CYP1A1 or 1A2, and hence they are unlikely to be carcinogenic or mutagenic. Furthermore, none of these chemicals had spatial parameters critical for substrates of CYP2E, and they are therefore unlikely to induce the formation of reactive oxygen species (ROS) or to initiate or promote malignancy or toxicity by mechanisms involving ROS. However, citral, and others of these terpenes, are known to undergo metabolism to carboxylic acids that may induce CYP4, and are therefore possible inducers of hepatic peroxisomal proliferation at high dosage, which may have implications for possible hepatotoxicity.

Animals↗
PubMed1994

Molecular modelling of cytochrome CYP1A1: a putative access channel explains differences in induction potency between the isomers benzo(a)pyrene and benzo(e)pyrene, and 2- and 4-acetylaminofluorene.

The present studies were undertaken to provide a rationale for the observation that benzo(a)pyrene and 2-acetylaminofluorene induce the hepatic CYP1A1 protein, whereas their non-carcinogenic isomers benzo(e)pyrene and 4-acetylaminofluorene are, at best, relatively very weak inducers. Using amino acid sequence alignment, a molecular model of the CYP1A1 was constructed by analogy to CYP101, the bacterial protein for which the 3-dimensional structure is known from X-ray crystallographic analysis. The putative structure of the active site of the CYP1A1 protein shows the presence of two phenylalanine residues preferentially aligned in parallel orientation, presumably functioning as a 'sieve' for planar molecules, the established substrates of CYP1A1. The molecular dimensions of this putative access channel show a width and depth of 8.321 and 3.261 A, respectively. The width of 4-acetylaminofluorene, 8.794 A, and benzo(e)pyrene, 9.153 A, precludes their passage through this channel access in contrast to benzo(a)pyrene and 2-acetylaminofluorene having a width of 7.150 and 5.283 A, respectively, explaining their difference in CYP1A1 induction potential.

2-Acetylaminofluorene↗
PubMed1994

Tocolysis with indomethacin increases the incidence of necrotizing enterocolitis in the low-birth-weight neonate.

OBJECTIVE: The null hypothesis states that prolonged antenatal indomethacin exposure within 24 hours of delivery does not increase the incidence of necrotizing enterocolitis in the low-birth-weight neonate. STUDY DESIGN: The neonates of patients receiving indomethacin tocolysis admitted in preterm labor (N = 56) were compared with the neonates of preterm labor patients who received no indomethacin tocolysis (N = 703). These neonatal groups were then compared with regard to gestational age at delivery, birth weight, mode of delivery, antenatal magnesium and steroid exposure, incidence of respiratory distress syndrome, perinatal depression, sepsis, umbilical catheterization, and feeding rates and volumes. The overall incidence of necrotizing enterocolitis, mortality secondary to necrotizing enterocolitis, and the intervals from delivery and feeding to necrotizing enterocolitis diagnosis were also compared. The association between necrotizing enterocolitis and the duration of indomethacin exposure and the interval from exposure to delivery for both the indomethacin and control groups was determined. RESULTS: The incidence of necrotizing enterocolitis in neonates who were delivered within 24 hours of maternal indomethacin therapy was 20% compared with 9% in the control group (p = 0.005). The incidence of necrotizing enterocolitis in neonates with > 48 hours of antenatal indomethacin exposure was 26.4% compared with 4.1% in those with < 48 hours exposure (p = 0.042). The interval from first feeding to necrotizing enterocolitis development was significantly shorter in the indomethacin group versus the control group (2.1 +/- 3.0 vs 6.8 +/- 6.3 days) (p = 0.001), as was the mean interval from delivery to development of necrotizing enterocolitis (10.2 +/- 3.7 vs 15.2 +/- 3.8 days) (p = 0.019). CONCLUSIONS: Antenatal indomethacin exposure occurring within < or = 24 hours of delivery and of at least 48 hours' duration is associated with a significant increase in the incidence of necrotizing enterocolitis in the low-birth-weight neonate.

Birth Weight↗
PubMed1994

Comparison of the hepatic effects of coumarin, 3,4-dimethylcoumarin, dihydrocoumarin and 6-methylcoumarin in the rat.

The mechanism of coumarin-induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of three coumarin derivatives, namely 3,4-dihydrocoumarin (DHC), 3,4-dimethylcoumarin (3,4-DMC) and 6-methylcoumarin (6-MC). Male Sprague-Dawley rats were fed either control diet or diets containing 0.5 or 0.75% coumarin, 0.76% DHC, 0.6 or 0.9% 3,4-DMC or 0.82% 6-MC for 13 wk. The dietary levels of 0.5% coumarin and 0.6% 3,4-DMC, were equimolar (3.43 mmol/100 g diet), as were the dietary levels of 0.75% coumarin, 0.76% DHC, 0.9% 3,4-DMC and 0.82% 6-MC (5.14 mmol/100 g diet). All treatments resulted in an increase in relative liver weight, but only coumarin increased plasma alanine aminotransferase and aspartate aminotransferase activities. Morphological examination of liver sections from coumarin treated rats revealed vacuolation of centrilobular hepatocytes and bile duct hyperplasia. Cholangiofibrosis was also observed, particularly in rats given 0.75% coumarin. Treatment with DHC produced no abnormalities, whereas a slight hypertrophy of centrilobular hepatocytes was observed in some 3,4-DMC treated animals and a slight vacuolation of individual hepatocytes was noted in some 6-MC treated rats. DHC, 6-MC and particularly 3,4-DMC treatment resulted in an induction of cytochrome P-450 dependent mixed function oxidase enzyme activities. All treatments induced hepatic GSHS-transferase and gamma-glutamyltransferase activities, induction being most marked in rats given coumarin and 6-MC. These results provide further evidence that coumarin-induced hepatotoxicity in the rat is due to the formation of a 3,4-epoxide intermediate.

Animals↗
PubMed1994

Interaction of a series of nitriles with the alcohol-inducible isoform of P450: computer analysis of structure-activity relationships.

1. Structural studies are reported on a series of 20 nitriles of varying rates of P4502E-mediated oxidative metabolism. 2. Parameters of molecular and electronic structure have been calculated for the generation of quantitative structure-activity relationships (QSARs) with the rates of oxidative metabolism of the nitriles, and with their acute toxicity. 3. Correlations between molecular polarizability, excitation energy and biological activity are presented as a result of QSAR analysis.

Biotransformation↗
PubMed1994

Inhibition of rat hepatic aryl hydrocarbon hydroxylase activity by a series of 7-hydroxy coumarins: QSAR studies.

1. Molecular orbital calculations, by the Modified Intermediate Neglect of Differential Overlap (MINDO/3) method, of a series of twenty-five 8-acyl-7-hydroxy coumarins show that the inhibition of aryl hydrocarbon hydroxylase (AHH) activities (cytochrome P4501, CYP1 activity, primarily CYP1A1) for 23 of these compounds is related to their structural parameters. The two remaining compounds are the only chlorinated derivatives; these are inactive towards the AHH system and were excluded from the quantitative structure-activity relationship (QSAR) analysis. 2. The results of multiple regression analyses show that AHH activity is dependent on the energy of the highest occupied molecular orbital, E(HOMO), in a single variable expression for the 23 compounds. However, a three-variable expression involving superdelocalizabilities provides a more significant correlation with biological activity. 3. The inactivity of the two chlorinated derivatives can be rationalized in terms of their low degree of molecular planarity, as estimated by the area/depth2 parameter, which presumably precludes them from interaction with CYP1.

Animals↗
PubMed1993

The effect of colonization with group B streptococci on the latency phase of patients with preterm premature rupture of membranes.

OBJECTIVE: Our purpose was to determine whether colonization of pregnant women with group B streptococci shortens the latency time from rupture of membranes to delivery in patients with preterm premature rupture of membranes. STUDY DESIGN: All patients transferred to Long Beach Memorial Women's Hospital with the diagnosis of preterm premature rupture of the membranes were prospectively recorded. The patients included in the study were transferred between Jan. 1, 1986, and June 30, 1991. Data were collected in regard to various obstetric characteristics, the presence or absence of a digital vaginal examination, tocolytic usage, antibiotic usage, and results of the culture for group B streptococci. The latency period was defined as days from membrane rupture to delivery. Patients with multiple gestations, cerclage in place, advanced labor on admission, or an indicated delivery on admission were excluded from data analysis. Patients with a positive culture for group B streptococci were then compared with those having a negative culture in regard to latency time after membrane rupture. RESULTS: The study population was made up of 332 patients. Forty-three (13%) were positive for group B streptococci; they were compared with 289 that were culture negative. There was no difference in the latency period from membrane rupture to delivery when we controlled for digital vaginal examinations and antibiotic usage. In addition, all other comparisons between the two groups were not significant. CONCLUSION: When the presence of a digital vaginal examination, antibiotic usage, and tocolytic usage are controlled for, colonization with group B streptococci by itself does not appear to affect the latency time from premature rupture of membranes to delivery.

Delivery, Obstetric↗
PubMed1993

Use of Amniostat-FLM in detecting the presence of phosphatidylglycerol in vaginal pool samples in preterm premature rupture of membranes.

OBJECTIVE: The presence of phosphatidylglycerol in amniotic fluid from the vaginal pool has been established as a reliable marker of pulmonary maturity in pregnancies complicated by preterm premature rupture of membranes because its presence is not affected by contaminants. This study was undertaken to determine the distribution of positive phosphatidylglycerol relative to gestational age from vaginal pool amniotic fluid samples and to assess the efficacy and accuracy of the Amniostat-FLM (Hana Biologics; Irvine Scientific after Sept. 14, 1989), an antibody agglutination method for rapidly detecting phosphatidylglycerol. STUDY DESIGN: All singleton nondiabetic pregnancies between 26 and 36 weeks with premature rupture of membranes from whom a vaginal pool sample was obtained were studied. The percent positive by gestational age was analyzed. The neonates that were delivered with a positive phosphatidylglycerol were evaluated for the presence of hyaline membrane disease and other immediate sequelae of prematurity. RESULTS: Of the 201 vaginal pool amniotic fluid samples assayed for phosphatidylglycerol with the Amniostat-FLM procedure, 18% (36/201) were positive for phosphatidylglycerol and none of the delivered infants developed hyaline membrane disease. CONCLUSION: The Amniostat-FLM seems to be accurate in predicting pulmonary maturity from vaginal pool samples.

Agglutination Tests↗
PubMed1993

Validation of a novel molecular orbital approach (COMPACT) for the prospective safety evaluation of chemicals, by comparison with rodent carcinogenicity and Salmonella mutagenicity data evaluated by the U.S. NCI/NTP.

The molecular dimensions and electronic structures of 100 chemicals of structural diversity have been determined from molecular orbital calculations and molecular mechanics. From these parameters of molecular structure, those chemicals that are likely substrates of cytochromes P4501 and P4502E have been identified by the computer-optimized molecular parametric analysis of chemical toxicity (COMPACT) programme, and their potential toxicity, mutagenicity and carcinogenicity evaluated. The degree of correlation between COMPACT prediction of toxicity and rodent two species life-span carcinogenicity data is estimated to be 92%, and between COMPACT and Salmonella mutagenicity (Ames test) data is 64%. Anomalous rodent carcinogens are rationalized on the basis of biochemical mechanisms of metabolism, genotoxicity and carcinogenicity. Correlation of the Ames test data with rodent carcinogenicity data was 64%, but correlation of COMPACT plus Ames data versus rodent carcinogenicity data provided the highest correlation of 94%.

Animals↗
PubMed1993

Computer modelling in predicting carcinogenicity.

The cytochrome P450-dependent mixed-function oxidases are the most important enzyme system in the oxidation of chemicals to their reactive intermediates which then interact with cellular components to provoke toxicity and carcinogenicity. These enzymes comprise a multifamily of proteins, two families of which, namely CYP1A and CYP2E, activate planar and small molecular weight compounds, respectively. A computer graphic procedure (COMPACT) has been developed which, based on the molecular shape and electronic structure of the chemical, determines whether the chemical will interact with these two particular cytochrome P450 families and thus be metabolized to toxic and carcinogenic intermediates. As the basal levels of these enzyme families are low, the ability of the chemical to induce them selectively, on repeated administration, is an important determinant of its carcinogenic potential. Inductive capability may be determined in short-term experiments (ENACT) utilizing a small number of animals. Thus the combination of COMPACT and ENACT provides a rapid and inexpensive means for the preliminary screening of chemicals, before the long term and expensive rodent lifetime bioassays are undertaken.

Animals↗
PubMed1993

Interaction of some peroxisome proliferators with the mouse liver peroxisome proliferator-activated receptor (PPAR): a molecular modelling and quantitative structure-activity relationship (QSAR) study.

1. The three-dimensional structure of a portion of the ligand-binding domain of the mouse liver peroxisome proliferator-activated receptor (PPAR) described by Issemann and Green (1990) has been modelled from amino acid sequence data. 2. By inspection of the three-dimensional structure of the portion of the PPAR ligand-binding domain, a putative binding site for peroxisome proliferators, consisting of one isoleucine, one lysine and two phenylalanine moieties (residues 354, 358, 359 and 361, respectively), has been identified. 3. The interaction of 12 peroxisome proliferators with the putative PPAR binding site has been investigated and energetics of binding calculated from ligand-bound and ligand-free receptor geometries. 4. The interaction data have been used to establish quantitative structure-activity relationships (QSARs) between peroxisome proliferator binding and either PPAR activation in COS1 cells or induction of palmitoyl-CoA oxidation in rat hepatocyte cultures. 5. The results are discussed in terms of the role of PPAR in the mechanism of initiation of peroxisome proliferation in rodent liver.

Amino Acid Sequence↗
PubMed1992

The sequence homologies of cytochromes P-450 and active-site geometries.

The amino acid sequence alignment of 16 cytochrome P-450 proteins representative of the major families is reported. The sequence matching process has been carried out on the basis of maximum homology by residue type, retention of secondary structure and minimization of deletions/insertions except where additional loop regions exist. From the starting point of known reported sequence homology matching from the literature, a realignment on the basis of conserved residues involved in both structure and function gives rise to a self-consistent set of sequences which correlates with known mechanistic and structural data. Once fitted, these archetypal sequences form a straightforward template for the alignment of all P-450 subfamilies. Computer modelling of the active-site regions constructed from homology with the bacterial form of the enzyme (P-450CAM) evinces the correct substrate specificity. Furthermore, the construction of the macromolecular assembly of components of the cytochrome P-450 system on the microsomal endoplasmic reticular membrane is presented from the evidence of site-directed mutagenesis, analysis by molecular probes, X-ray crystallography and molecular modelling.

Amino Acid Sequence↗
PubMed1992

Antimutagenicity of ellagic acid towards the food mutagen IQ: investigation into possible mechanisms of action.

The ability of the plant phenol ellagic acid to inhibit the mutagenicity of the food mutagen IQ was evaluated using Salmonella typhimurium strain TA98 in the Ames mutagenicity test. Ellagic acid caused a concentration-dependent decrease in the S-9- and microsome-mediated mutagenicity of IQ. The plant phenol did not interact directly with the IQ-derived mutagenic species and did not modify the cytosol-mediated activation of the promutagen. At the concentrations used in the mutagenicity studies, ellagic acid failed to inhibit microsomal mixed-function oxidase activity, including that mediated by the P450I family responsible for the bioactivation of IQ, despite being an essentially planar molecule as indicated by computer-graphic analysis. The inhibitory effect of ellagic acid was independent of its ability to chelate Mg2+. However, pre-incubation of ellagic acid with the bacteria, followed by removal of the plant phenol, did not completely prevent the inhibitory effect of the phenol on the mutagenicity of IQ. Intraperitoneal administration of ellagic acid to rats caused a decrease in total cytochrome P-450 levels and related activities as well as in cytosolic glutathione S-transferase activity. Finally, the possibility that the reported anticarcinogenic action of ellagic acid reflects nothing more than non-selective destruction of hepatic cytochromes P-450, and thus reduced chemical activation, is considered.

Animals↗
PubMed1992

Activation of 15-lipoxygenase by low density lipoprotein in vascular endothelial cells. Relationship to the oxidative modification of low density lipoprotein.

Oxidatively-modified low density lipoprotein (LDL) is thought to play a significant role in the formation of lipid-laden macrophages, the primary cellular component of atherosclerotic fatty lesions. Recently, lipoxygenases have been implicated as a major enzymatic pathway involved in rabbit endothelial cell-mediated LDL modification. We investigated the effect of LDL on porcine aortic endothelial cell (PAEC) and human umbilical vein (HUVEC) and aortic endothelial cell (HAEC) lipoxygenase activity. By thin layer chromatography, we observed that human LDL stimulated the metabolism of radiolabeled arachidonic acid to 12 + 15-hydroxyeicosatetraenoic acid (HETE) in indomethacin-treated PAEC. Furthermore, radiolabeled linoleic acid, a specific substrate for the 15-lipoxygenase, was metabolized to its respective product 13-hydroxyoctadecadienoic acid (13-HODE) in the presence of LDL. Increased product formation in both studies was inhibited by the lipoxygenase blockers nordihydroguaiaretic acid (NDGA) and RG 6866. 15-HETE was confirmed as the predominant HETE product in LDL-treated cells by high performance liquid chromatography. Both porcine- and human-derived LDL stimulated the CL release of 15-HETE from cells as determined by radioimmunoassay. Release of immunoreactive 15-HETE was inhibited by NDGA, RG 6866, and 5,8,11,14-eicosatetraynoic acid (ETYA) but not by the selective 5-lipoxygenase inhibitor RG 5901. These lipoxygenase inhibitors had similar effects on the modification of LDL. Our results suggest that the oxidative modification of LDL by endothelial cells may be mediated in part through activation of 15-lipoxygenase.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗