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Biomedical subjects

D Roy

Publications and source records attributed to D Roy.

At least 217 records · Page 12Linked to original sources
PubMed1992

Evaluation of pan masala for toxic effects on liver and other organs.

The acute and chronic oral toxicity of pan masala (betel quid without betel leaf) was assessed in gavage studies in rats. Clinical parameters (liver and serum glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase and alkaline phosphatase) and organ weights were measured. The results indicate that chronic feeding of pan masala impaired liver function, as indicated by changes in enzyme activity, and decreased relative weights of the gonads and brain.

Animals↗
PubMed1992

Elevation of protooncogene messenger RNAs in estrogen-induced kidney tumors in the hamster.

Cellular oncogenes such as c-fos, c-jun and c-myc are expressed prior to estrogen-induced growth of normal target tissues such as rodent uterus. Transient increases in the levels of these genes are induced by the administration of estradiol and are followed by DNA replication. In this study, we examined the expression of these three oncogenes in estradiol-induced kidney tumors in Syrian hamsters in order to understand mechanistic aspects of hormonal carcinogenesis. Kidney tumors were induced in all male Syrian hamsters treated chronically with estradiol for 7 or 9 months, whereas neoplasms were not detected in animals treated for 5 months. mRNA levels of fos, myc and jun were elevated 15-, 4- and 6-fold respectively in kidney tumors of estradiol-treated hamsters (9 months) compared with age-matched untreated control kidneys. The expression of all three protooncogenes was also increased in the kidney tissue surrounding tumors, though there was no consistent pattern in the ratios of transcripts in the tumor and kidney tissues. After 7 months of estrogen treatment, kidney tumors also contained elevated amounts of c-fos, c-jun and c-myc transcripts at levels comparable with older tumors. In abdominal metastases of hamster kidney tumors, mRNA levels of fos, myc and jun were elevated 9-, 12- and 3-fold respectively over control levels. In kidneys of hamsters treated with estradiol for 5 months, in which tumors were not yet detected, the expression of protooncogenes was slightly increased. Ratios of c-fos, c-myc and c-jun in estrogen-treated (5 months) over control tissue were 1.4, 1.1 and 1.3 respectively. Overexpression of cellular oncogenes such as c-fos, c-jun and c-myc may have played a role in the induction and growth of kidney tumors by estradiol in hamsters.

Animals↗
PubMed1992

Examination of microsomal cytochrome P450-catalyzed in vitro activation of o-phenylphenol to DNA binding metabolite(s) by 32P-postlabeling technique.

It has been previously reported that the reactive metabolites phenylsemiquinone and phenylbenzoquinone are generated during microsomal cytochrome P450-catalyzed redox cycling of o-phenylphenol (OPP). However, covalent modification of DNA by OPP-reactive metabolites has yet not been demonstrated. In the present study we have investigated the covalent binding in DNA by OPP-reactive metabolites using 32P-postlabeling. Analysis of adducts by 32P-postlabeling in products of chemical reaction of DNA with phenylbenzoquinone revealed four major and several minor adducts. The chemical reaction of deoxyguanosine 3'-phosphate with phenylbenzoquinone also showed four major adducts. The chromatographic mobility of major adducts of deoxyguanosine 3'-phosphate-phenylbenzoquinone was identical to that of major adducts of DNA-phenylbenzoquinone. The major adducts are demonstrated to be stable. The total covalent binding in deoxyguanosine 3'-phosphate by phenylbenzoquinone (686,000-687,000 amol/nmol nucleotide) was higher than that observed in DNA (26,500-28,000 amol/nmol nucleotides). Reaction of DNA with OPP or a hydroxylated metabolite of OPP, phenylhydroquinone, in the presence of microsomes and NADPH or cumene hydroperoxide showed four major adducts. Adduct formation in DNA by OPP or phenylhydroquinone in the presence of the microsomal activation system was drastically decreased by known inhibitors of cytochrome P450. The chromatographic mobility of major adducts in DNA by OPP or phenylhydroquinone in the presence of microsomal activation system matched with those major adducts observed in deoxyguanosine 3'-phosphate or DNA reacted with pure phenylbenzoquinone. These data demonstrate that OPP or phenylhydroquinone, a hydroxylated metabolite of OPP, is able to bind covalently to DNA in the presence of a microsomal cytochrome P450 activation system. Phenylbenzoquinone is one of the DNA-binding metabolite(s) of OPP. It is concluded that OPP is genotoxic in an in vitro system and genotoxicity produced by OPP-reactive metabolites may play a role in OPP-induced cellular toxicity or cancer.

Animals↗
PubMed1992

Success, safety, and late electrophysiological outcome of low-energy direct-current ablation in patients with the Wolff-Parkinson-White syndrome.

BACKGROUND: Percutaneous ablation of accessory pathways with the use of a defibrillator can be accomplished with high-energy direct-current (DC) shocks of 150-400 J, but complications include cardiac tamponade and sudden cardiac death, mostly resulting from significant electrical arcing and barotrauma. A new low-energy DC power source with a brief time-constant capacitive discharge delivers shocks of 2-40 J and eliminates or greatly reduces arcing. This report describes our initial experience with this device in 60 consecutive patients (mean age, 34 years; range, 9-67 years) with Wolff-Parkinson-White syndrome. Accessory pathways were located in the left free wall in 36 patients, in the right free wall in two, were posteroseptal in 18, and anteroseptal in four. Most patients (77%) had their initial diagnostic electrophysiological study and catheter ablation during the same session. METHODS AND RESULTS: Selective ablation of accessory pathways was successful in 55 patients (92%). The mean cumulative energy was 312 +/- 284 J and the mean creatine kinase MB peak (normal, 0-30 units) was 42 +/- 27 units. Patients with left free wall accessory pathways required less procedure time for ablation (2.7 +/- 0.8 versus 3.6 +/- 1.5 hours, p less than 0.0007) and less fluoroscopy time (46 +/- 24 versus 66 +/- 33 minutes, p less than 0.002). Complications were limited to transient pericarditis (three patients), one iliac artery dissection, and cardiac tamponade probably caused by catheter repositioning in the coronary sinus (one patient). An electrophysiological study was repeated in 50 of the 55 successful cases at a mean of 9 +/- 5 months. This study was normal in 48 of 50 (96%) patients. CONCLUSIONS: Low-energy DC ablation is safe and effective treatment for accessory pathways in children and adults. The long-term outcome is excellent as documented by electrophysiological restudy.

Adult↗
PubMed1992

Rate-dependent effects of diltiazem on human atrioventricular nodal properties.

BACKGROUND: Tachycardia enhances the channel-blocking effects of antiarrhythmic drugs. In contrast to the extensive data regarding the rate-dependent effects of sodium channel blockers in humans, little is known about the frequency-dependent effects of calcium channel blockers on human atrioventricular (AV) nodal properties. Accordingly, the purpose of this study was to evaluate the importance of heart rate in modulating the electrophysiological effects of diltiazem in humans. METHODS AND RESULTS: Electrophysiological studies were performed in 25 patients. Sinus node, atrial, and AV nodal function were evaluated at multiple atrial rates under control conditions and after administration of one of three intravenous doses of diltiazem designed to produce low, intermediate, and high stable plasma concentrations (designated doses 1, 2, and 3, respectively). Results were analyzed in terms of the longest and shortest cycle lengths obtainable in each patient under control and drug conditions. Plasma concentrations of diltiazem were stable and averaged 43 +/- 4, 73 +/- 6, and 136 +/- 11 ng/ml for doses 1, 2, and 3, respectively. Sinus node recovery time, intra-atrial conduction time, atrial effective refractory period, and HV interval were unaffected by diltiazem infusion. Effects of diltiazem were limited to changes in AV nodal parameters. Stable, dose-dependent increases in Wenckebach cycle length were observed after all three doses of diltiazem (increases of 54 +/- 13, 84 +/- 18, and 174 +/- 33 msec for doses 1, 2, and 3, respectively). Small nonsignificant increases in AH interval and atrioventricular effective refractory period (AVERP) were observed after dose 1 of diltiazem. At long cycle lengths, diltiazem caused modest increases in AH interval (3 +/- 4 and 25 +/- 8 msec for doses 2 and 3, respectively) and AVERP (36 +/- 12 and 70 +/- 25 msec). Drug effects were far greater at short cycle lengths (45 +/- 17 msec, 58 +/- 12 msec for AH interval and 80 +/- 24 msec, 163 +/- 41 msec for AVERP; p less than 0.05 versus values at long cycle lengths). At rapid rates, effects of diltiazem on AVERP substantially exceeded those on AV conduction, a result that could account for the beneficial effects of diltiazem during paroxysmal AV reentrant tachycardia by decreasing the excitable gap. CONCLUSIONS: Depressant effects of diltiazem on human AV nodal function are highly dependent on atrial rate; the rate-dependent actions on AV nodal refractoriness probably contribute to beneficial effects of diltiazem in patients with supraventricular arrhythmias.

Atrioventricular Node↗
PubMed1992

Elevated 4-hydroxylation of estradiol by hamster kidney microsomes: a potential pathway of metabolic activation of estrogens.

Characterization of enzymes mediating the formation of catecholestrogens (CE) by hamster kidney is of importance because of the proposed role of CE in renal cancer induced in this species by estrogens. We have reexamined the potential of hamster kidney to convert estradiol (E2) to 2- and 4-hydroxylated CE because of recent evidence of the limitations of assays used in previous studies, in particular in measuring 4-hydroxylation of estrogens. Under conditions optimized for NADPH-dependent activity, hamster kidney microsomes exhibited high levels of both E2-2- and E2-4-hydroxylase activities. Evidence that the two activities depend on different forms of cytochrome P-450 was obtained by the demonstration that 2- and 4-hydroxylation of E2 were affected differentially 1) by chronic treatment of hamsters with E2 and 2) by fadrozole hydrochloride, a selective cytochrome P-450 inhibitor. NADPH-dependent 2-hydroxylation of E2 from control and E2-treated hamsters, measured by a direct product isolation assay, was 1 order of magnitude higher (apparent maximum velocity, 24-32 and 6-12.5 pmol/mg protein.min in control and E2-treated hamsters, respectively) than that reported previously using radioenzymatic assays. NADPH-dependent 4-hydroxylation of E2 in controls approached and in E2-treated hamsters exceeded 2-hydroxylation of E2 (apparent maximum velocity, 17-21 and 7.5-19 pmol/mg protein.min in control and E2-treated hamsters, respectively). Thus, estrogen treatment reversed the ratios of NADPH-dependent E2-2-/4-hydroxylase activities by causing a much greater decline in 2- than 4-hydroxylation of E2 (P less than 0.007, by analysis of variance). Fadrozole hydrochloride caused a marked dose-dependent decrease in 2-hydroxylation of E2, in contrast to a small nondose-dependent inhibition of 4-hydroxylation. Under conditions optimized for peroxidatic organic hydroperoxide-dependent activity, hamster kidney microsomes generated 2- and 4-hydroxylated CE in similar amounts. The amounts of the two CE and, consequently, the ratios remained unaffected by estrogen treatment (1:0.9 and 1:1.0 in control and E2-treated hamsters, respectively). Thus, this study establishes that CE can be generated in the same tissue by three different pathways, i.e. NADPH-dependent E2-2-hydroxylase, NADPH-dependent E2-4-hydroxylase, and organic hydroperoxide-dependent E2-2/4-hydroxylase activities. We also show that these three activities can be regulated differentially and are, thus, probably mediated by different forms of cytochrome P-450. In hamster kidney, the potential to generate 4-hydroxylated CE metabolites with distinct properties could be a factor in this tissue's vulnerability to estrogen-induced carcinogenesis.

Animals↗
PubMed1992

Growth and activities of Lactococcus lactis in milk enriched with low mineral retentate powders.

The growth and activities of three strains of Lactococcus lactis ssp. cremoris (Wg2, E8, and HP) and their proteinase-negative variants were studied in skim milk enriched with three types of retentate powder. The performance of these strains in enriched milks was compared with that determined in reconstituted skim milk. Proteinase-positive strains of L. lactis ssp. cremoris exhibited higher maximum specific growth rates than protease-negative variants. Moreover, maximum specific growth rates of lactococci were lower in skim milk than in enriched milk with a high buffering capacity. The performance of proteinase-positive strains was better than that of proteinase-negative variants. Growth of proteinase-positive lactococci in milk media increased alpha-amino groups as determined by the increase of equivalent glutamic acid concentration. Available alpha-amino groups decreased with proteinase-negative variants. Proteinase-positive strain Wg2 exhibited the most proteolytic activity but showed the least specific overall productivity of lactic acid despite high biomass concentration in milk. Among proteinase-positive lactococci, strain E8 produced more lactic acid than other strains, and, among proteinase-negative variants, strain HP had the best specific overall productivity of lactic acid.

Animals↗
PubMed1992

Changes in protein and nonprotein thiol contents in bladder, kidney and liver of mice by the pesticide sodium-o-phenylphenol and their possible role in cellular toxicity.

Acute treatment of mice with Na-o-phenylphenol or phenylbenzoquinone, an electrophilic metabolite of o-phenylphenol, resulted in differential depletion of contents of protein and nonprotein thiols in bladder, kidney and liver. Maximum decrease in the levels of protein and nonprotein reduced thiols was observed in bladder (by both agents) and was followed by kidney (by both agents) and liver (phenylbenzoquinone only). The reason for this differential changes in reduced thiol contents remains to be understood. The content of protein and nonprotein disulfides was higher in bladder of mice treated with Na-o-phenylphenol compared to that observed in untreated mice bladder. Phenyl 2,5'-p-benzoquinone mediated in vivo depletion of nonprotein and protein thiols suggests that Na-o-phenylphenol treatment may decrease in vivo thiols via the formation of phenylbenzoquinone. Increased disulfide formation is considered to represent an index of oxidative stress produced by chemical. Increases in the level of protein and nonprotein disulfides in bladder suggest as observed in this study that administration of Na-o-phenylphenol to mice produced oxidative stress in bladder. Products of redox cycling of xenobiotics are known to cause cellular toxicity via altering the homeostasis of thiol status. Therefore, it is concluded that decreases in protein thiol contents either via alkylation and/or oxidation of sulfhydryl groups of proteins and increases in disulfide contents presumably by products of redox cycling of Na-o-phenylphenol may play a role in Na-o-phenylphenol-induced cellular toxicity.

Animals↗
PubMed1991

Xanthine oxidase-catalyzed reduction of estrogen quinones to semiquinones and hydroquinones.

Metabolic redox cycling between the stilbene estrogen diethylstilbestrol (DES) and diethylstilbestrol-4',4"-quinone (DES Q) has been demonstrated previously. The xanthine and xanthine oxidase-catalyzed reduction of estrogen quinone has been studied in this work to understand the role of metabolic redox cycling in estrogen metabolism. Xanthine and xanthine oxidase catalyzed the reduction of DES Q to 44% Z-DES and 9% E-DES. This reaction was inhibited by the addition of superoxide dismutase or by a lack of oxygen (under anaerobic conditions). DES Q was also reduced in a non-enzymatic reaction by superoxide radicals generated by potassium superoxide and crown ether. The reaction between the O2-. and DES Q was also investigated by an electron spin resonance spin-trapping technique. The superoxide anion generated in an oxygen-saturated xanthine and xanthine oxidase system was detected as 5,5-dimethyl-1-pyrroline-1-oxide-superoxide adduct. The addition of DES Q or 2,3-estradiol quinone totally inhibited the formation of this adduct. The reduction of DES Q by superoxide radicals was taken as evidence that this reaction was one possible mechanism of xanthine and xanthine oxidase-mediated reduction. In addition, reduction of DES Q by direct electron transfer to quinone by the enzyme may also occur. The intermediate formation of semiquinone free radicals in the reduction is implied by the nature of the single electron transfer reactions and, in addition, has been demonstrated for the catechol estrogen by electron spin resonance measurements. It is concluded that the reduction of estrogen quinones to their hydroquinones by xanthine oxidase occurs by both one electron transfer to the quinone and by formation of superoxide which then reduces the quinone.

Diethylstilbestrol↗
PubMed1991

Elevated 8-hydroxydeoxyguanosine levels in DNA of diethylstilbestrol-treated Syrian hamsters: covalent DNA damage by free radicals generated by redox cycling of diethylstilbestrol.

The generation of free radicals by microsome-mediated redox cycling between catechol estrogens or diethylstilbestrol and their corresponding quinones has previously been demonstrated in vitro. However, the reaction of free radicals with DNA has not yet been detected in animals treated with estrogen and is the subject of this investigation. The reaction of guanine bases of DNA with hydroxyl radicals to form 8-hydroxydeoxyguanosine has been used as a monitor of free radical generation in kidney and liver of Syrian hamsters, a species prone to estrogen-induced carcinogenesis. Prior to in vivo measurements, the in vitro hydroxylation of guanine bases of DNA under conditions of redox cycling of estrogen was investigated. In incubations of DNA or deoxyguanosine with hamster kidney microsomes, NADPH, and diethylstilbestrol 4',4"-quinone, the hydroxylation of guanine bases of free deoxyguanosine or of DNA was 50 to 100% higher than in controls. When incubations were carried out in the presence of iron(III) chloride, the hydroxylation of guanine bases was 2.5- or 10-fold higher than control values. There was a 65% increase from control values in levels of 8-hydroxydeoxyguanosine in liver DNA of hamsters treated with 20 mg/kg/day diethylstilbestrol for 3 days and 100 mg/kg on the 4th day. In hamsters treated chronically with diethylstilbestrol implants for 15 days, 8-hydroxydeoxyguanosine levels more than doubled from control values in kidney but not liver DNA. Treatment of hamsters with estradiol for various time periods did not induce any changes in levels of hydroxylated guanine in either kidney or liver. It was concluded that in vitro and in vivo redox cycling of diethylstilbestrol hydroxylated guanine bases in DNA.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1991

Determination of estradiol 2- and 4-hydroxylase activities by gas chromatography with electron-capture detection.

A highly sensitive assay has been developed for measuring the rate of formation of 2-hydroxyestradiol and 4-hydroxyestradiol from estradiol by microsomal preparations. Catechol estrogens were converted to heptafluorobutyryl esters, which were separated by capillary column gas chromatography and quantified using electron-capture detection. 2-Hydroxyestradiol 17-acetate was used as an internal standard. The identity of catechol estrogen derivatives was verified by gas chromatography-mass spectrometry using negative-ion chemical ionization. Estrogens were identified by negative molecular ions and/or by characteristic fragments. This procedure permits quantification of catechol estrogens at the subpicogram level. The assay was validated by comparing estrogen 2- and 4-hydroxylase activities in microsomes from hamster and rat liver with values reported previously.

Animals↗
PubMed1991

Computer assisted analysis of hand radiographs in infantile hypophosphatasia carriers.

Hand radiographs of 49 carriers of infantile hypophosphatasia and 67 non-carriers were evaluated using two Apple IIe Computer Programs and an Apple Graphics Tablet. CAMPS (1) was used to determine the bone lengths and calculate the metacarpophalangeal profiles. A newly developed program (ADAM) was used to determine bone density based on percent cortical area of the second metacarpal. Carriers of infantile hypophosphatasia had significantly less dense bones.

Adolescent↗
PubMed1991

Clinical and angiographic features and prognostic significance of early postinfarction angina with and without electrocardiographic signs of transient ischemia.

PURPOSE: The goal of the study was to characterize the clinical and angiographic characteristics and the prognostic significance of early postinfarction angina associated or unassociated with ST-T changes. PATIENTS AND METHODS: Four hundred forty-nine consecutive patients surviving an acute myocardial infarction and catheterized before hospital discharge were included. They were closely monitored in the coronary care unit and a 12-lead electrocardiogram (ECG) was promptly obtained before the administration of nitroglycerin whenever chest pain suggestive of ischemia occurred. Complete follow-up information was obtained for all patients a mean of 14 +/- 8 months after the qualifying infarction. RESULTS: Early postinfarction angina occurred in 164 patients. Transient ST-T changes were documented during pain in 79 patients and were absent in 85. Compared with patients without postinfarction angina, patients with angina without ST-T changes were older and had a more frequent past history of angina (42% versus 28%, p = 0.01). They also more often had a non-Q-wave myocardial infarction with lower peak creatine kinase blood level elevation. At angiography, patients with angina had more extensive coronary artery disease (1.9 +/- 0.8 diseased vessels per patient versus 1.6 +/- 0.8, p less than 0.05) and more left ventricular segments at jeopardy by a significant coronary artery stenosis (1.5 +/- 1.1 versus 1.2 +/- 1.1, p less than 0.05). The presence of ST-T changes during chest pain was associated with a further increase in the severity of coronary artery disease (2.1 +/- 0.8 diseased vessels per patient, p less than 0.05) and with a less well-developed collateral circulation (18% versus 34% of patients, p = 0.01) that was more often compromised by a coronary artery stenosis (22% versus 8% of patients, p = 0.008). In-hospital infarct extension occurred in 2% of patients without angina, 3.5% of patients with angina without ECG changes, and 28% of patients with angina and ST-T changes (p less than 0.01). The 2-year survival was similar in the first two groups (90% and 96%), and poorer (83%, p = 0.02) in patients with ST-T changes. Survival rates without myocardial infarction were respectively 80%, 78%, and 67% (p less than 0.004). CONCLUSION: A gradient in the severity of coronary artery disease and in the extent of myocardium at jeopardy exists from patients with no postinfarction angina to patients with angina and to patients with angina accompanied by ECG signs of ischemia. The presence of ST-T changes during pain indicates a much less favorable clinical outcome.

Angina Pectoris↗
PubMed1991

Cytochrome b5-mediated redox cycling of estrogen.

Previously, we have demonstrated microsomal cytochrome P450-catalyzed redox cycling of estrogens. In this study, we investigated the role of cytochrome b5 in redox cycling in order to obtain a full understanding of enzymatic contributions to redox reactions of estrogens. Pure cytochrome P450c and hydrogen peroxide or cumene hydroperoxide oxidized diethylstilbestrol (DES) to diethylstilbestrol-4',4"-quinone (DES Q). This oxidation by H2O2 was doubled by addition of cytochrome b5 to cytochrome P450c (molar ratio of 1:4), but did not proceed with cytochrome b5 alone. The stimulation by cytochrome b5 of the cytochrome P450c-catalyzed oxidation of DES to DES Q occurred via modulation of the Vmax of cytochrome P450c rather than of the Km. DES Q was reduced to DES by purified cytochrome b5 and NADH-dependent cytochrome b5 reductase. Pretreatment of microsomes with an antibody to cytochrome b5 reductase inhibited microsomal NADH-dependent reduction of DES Q to DES by 55%. Cytochrome b5 likely participates in the oxidation of DES to DES Q by interacting with cytochrome P450c and in the reduction of DES Q to DES by interacting with cytochrome b5 reductase. Thus, the study demonstrates that cytochrome b5 plays an active role in biological oxidation and reduction reactions.

Animals↗