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P Upadhyaya

Publications and source records attributed to P Upadhyaya.

13 recordsLinked to original sources
PubMed1992

Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

The chemopreventive effect of 40% and 80% maximum tolerated dose (MTD) levels of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) administered in the diet during the initiation phase (2 weeks before, during, and up to 3 days after carcinogen administration) and the post-initiation phase (3 days after carcinogen treatment until termination) of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD of p-XSC was determined in male F344 rats and found to be 50 ppm. Beginning at 5 weeks of age, all animals were divided into various experimental groups (42 rats/group) and fed the high-fat semipurified diet or diets containing 20 (40% MTD) and 40 (80% MTD) ppm p-XSC. At 7 weeks of age, all animals (30 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM (15 mg/kg body weight/week for 2 weeks). Three days after the second injection of AOM or vehicle (normal saline), groups of animals fed the p-XSC diets and control diet were transferred, respectively, to control diet and p-XSC diets and continued on these diets until the termination of the study. All animals were necropsied during the 36th week after AOM treatment. Colonic mucosal prostaglandin E2 and selenium-dependent glutathione peroxidase were measured in animals fed the control and p-XSC diets at the termination of the study. The results indicate that 40 ppm p-XSC administered during the initiation phase significantly inhibited the colon tumor incidence (percentage of animals with tumors). Dietary p-XSC administered at 20 and 40 ppm levels during the initiation phase significantly inhibited colon tumor multiplicity (tumors/animal and tumors/tumor-bearing animal). Colon tumor incidence and multiplicity were significantly reduced in groups fed 20 and 40 ppm p-XSC diets at the postinitiation phase of carcinogenesis. Colonic mucosal selenium-dependent glutathione peroxidase activity was increased, and prostaglandin E2 was reduced in animals fed the p-XSC diet compared to animals fed the control diet. Whereas the precise mechanisms of p-XSC-induced inhibition of colon carcinogenesis remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis and selenium-dependent glutathione peroxidase activity.

Adenocarcinoma↗
PubMed1992

Inhibition of 7,12-dimethylbenz(a)anthracene-induced tumors and DNA adduct formation in the mammary glands of female Sprague-Dawley rats by the synthetic organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate.

We synthesized a novel organoselenium compound, 1,4-phenylenebis(methylene)selenocyanate (XSC), possessing low toxicity by comparison with inorganic Na2SeO3, and several other synthetic organoselenium compounds (K. El-Bayoumy, Cancer Res., 45: 3631-3636, 1985). We tested the effect of XSC treatment during the initiation phase on 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma formation. A semipurified high-fat diet containing 80 ppm of XSC (40 ppm as selenium) was fed to 6-wk-old virgin female Sprague-Dawley rats for 2 wk, starting 1 wk before and ending 1 wk after carcinogen treatment. At 7 wk of age, rats were given a single dose of DMBA (5 mg) in 0.2 ml of olive oil by gastric intubation; the experiment was terminated 16 wk later. The development of mammary tumors in those rats that received XSC-supplemented diets was significantly inhibited when compared with the control group (fed the same diet without XSC supplements). This was evident from tumor incidence (percentage of tumor-bearing rats, 88 versus 20) and multiplicity of tumors (mean number of tumors/rats, 3.96 versus 0.28). The finding that XSC acts as a chemopreventive agent in the DMBA mammary tumor model prompted us to examine the effect of dietary XSC on DMBA-DNA binding in both the liver and mammary tissue under conditions identical to those described above for the bioassay. Rats (four/group) were killed 6, 24, 48, and 168 h after [3H]DMBA (5 mg/rat; specific activity, 51.2 mCi/mM) administration. Liver and mammary tissue were obtained and DNA was isolated. Dietary XSC was found to inhibit total DMBA-DNA binding in the mammary tissue, but not in the liver. The most profound effect was observed at early time points, i.e., 24 to 48 h after [3H]DMBA administration. The inhibition in total binding was attributed to a reduction in the formation of the three major adducts derived from bay-region diol-epoxides of DMBA; these were identified as anti-diol-epoxide:deoxyguanosine, syn-diol-epoxide:deoxyadenosine, and anti-diol-epoxide:deoxyadenosine adducts on the basis of their chromatographic characteristics on high-pressure liquid chromatography and on a boronate affinity column. The inhibition of the DMBA-DNA binding in the target tissue provides a plausible explanation for the chemopreventive effect of XSC during the initiation stage of carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1992

Metabolism and DNA binding of 2-nitropyrene in the rat.

2-Nitropyrene (2-NP), a contaminant of ambient air, is a potent bacterial mutagen in the Ames assay and induces leukemia/lymphoma in female Sprague-Dawley rats. To understand the mechanistic basis for its tumorigenic activity, it is essential to elucidate the metabolic pathways of 2-NP in vivo. Such knowledge will also assist in developing analytical methods for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Thus, 2-nitro[U-4,5,9,10-14C]pyrene was synthesized and administered to male F344 rats by intragastric gavage at a dose of 30 mg (0.4 mCi/mM)/kg body weight. During the first 48 h, 57.5% of the dose was eliminated in the feces and 9.7% was eliminated in the urine. Correspondingly, after 168 h, 58.9 and 10.6% were excreted in feces and urine, respectively. Fecal metabolites (isolated amounts) included 6-hydroxy-2-acetylaminopyrene (19.5%), 6-hydroxy-2-aminopyrene (10.4%), 2-aminopyrene (10.0%), 2-acetylaminopyrene (0.8%), and unmetabolized 2-nitropyrene (10.0%). 6-Hydroxy-2-acetylaminopyrene, 6-hydroxy-2-aminopyrene, and 2-aminopyrene were identified as their acetyl derivatives by comparison of their chromatographic retention times, mass spectra, and UV spectra to those of synthetic standards. Urinary metabolites included 6-hydroxy-2-acetylaminopyrene (2.0%); glucuronide conjugates were tentatively identified (3.2%). The results of this study indicate that nitroreduction and ring oxidation are metabolic pathways in vivo. For DNA binding studies, rats were treated with 2-nitro[4,5,9,10-3H]pyrene [1.6 mg (598 mCi/mM)/kg body weight]. The levels of binding (pM bound/mg DNA) were as follows: 1.3, liver; 1.14, mammary tissue; 0.65, lung; 1.67, kidney; and 1.8, bladder. Upon high-performance liquid chromatographic analysis of the DNA hydrolysate (liver, mammary, and kidney), approximately 2.0% of the radioactivity coeluted with the synthetic markers derived from nitroreduction, N-(deoxyguanosin-8-yl)-2-aminopyrene and N-(deoxyadenosin-8-yl)-2-aminopyrene. Thus, simple nitroreduction of 2-NP does not significantly contribute to the total DNA binding of 2-NP metabolites in vivo. The significance of each pathway for the tumorigenic effects of 2-NP remains to be examined.

Air Pollutants↗
PubMed1992

Subchronic toxicity of benzyl selenocyanate and 1,4-phenylenebis(methylene)selenocyanate in F344 rats.

Chemopreventive agents benzyl selenocyanate (BSC) and 1,4-phenylenebis(methylene)selenocyanate (p-XSC) were fed in NIH-07 diet to male and female F344 rats (4, 2, and 0.5 mg/kg/day for BSC and 20, 10, and 5 mg/kg/day for p-XSC) for 13 weeks. Weight gains were depressed for male and female rats fed 4 and 2 mg/kg/day BSC, females fed 0.5 mg/kg/day BSC, and male rats fed 20 and 10 mg/kg/day p-XSC. At necropsy, no clear treatment-related lesions were noted, but dose-dependent hepatomegaly was observed in both sexes of BSC and p-XSC groups. Plasma transaminases AST and ALT were elevated in the higher dose groups, while hemoglobin, HCT, and RBC were reduced in most BSC and some p-XSC treatment groups. Plasma glucose was reduced in BSC-treated males. Significant histologic findings included moderate to severe hepatic centrilobular hypertrophy with fatty change in all males and females in the 4 mg/kg/day BSC groups and in 9/15 males and 3/15 females in the 2 mg/kg/day BSC groups. Dose-dependent, mild centrilobular hypertrophy with minimal fatty change was observed in the mid- and low-dose BSC groups and in all p-XSC groups. Mild to moderate renal tubular and interstitial nephritis occurred in the 4 mg/kg/day male BSC group. Dietary maximum tolerated dose levels for chemoprevention studies are 0.5 mg/kg/day (3.0 ppm Se) for BSC and 5 mg/kg/day (32.5 ppm Se) for p-XSC, compared to literature values of 2-3 ppm Se for Na2SeO3.

Animals↗
PubMed1992

Comparative tumorigenicity of nitrochrysene isomers in newborn mice.

6-Nitrochrysene (6-NC) is a potent lung and liver carcinogen in the newborn mouse assay. In this report, we extended our studies of the structure--tumorigenicity relationships of the mononitrochrysene isomers. We synthesized 1-NC, 2-NC and 3-NC by oxidation of the corresponding aminochrysenes with mCPBA; efforts to synthesize 4-NC and 5-NC from 4- and 5-aminochrysene were not successful. The tumorigenic activities of 1-NC, 2-NC, 3-NC and 6-NC were compared. Groups of mice were treated with the appropriate compounds in dimethylsulfoxide (DMSO) by i.p. injection on the 1st, 8th and 15th day of life. At a total dose of 100 nmol/mouse, 6-NC induced significant incidences and multiplicities of lung tumors in mice in both sexes; only males were susceptible to liver tumor induction. At 100 nmol/mouse, induction of lung and liver tumors by 1-NC, 2-NC and 3-NC was not significantly different from that observed in mice treated with DMSO. The results indicate that nitro substitution at the 6-position of chrysene is critical for strong tumorigenicity in the newborn mouse assay.

Animals↗
PubMed1991

Identification of the major metabolites and DNA adducts formed from 2-nitropyrene in vitro.

In contrast to 1-nitropyrene (1-NP), which is the most abundant nitropolycyclic aromatic hydrocarbon in numerous environmental sources, 2-nitropyrene (2-NP) has been detected only in the ambient air and not in direct emissions. Thus, 2-NP can be used as an indicator for monitoring human exposure to nitropolynuclear aromatic hydrocarbons in ambient air. Therefore, it is essential to determine the possible metabolic pathways of 2-NP. The metabolism of 2-NP by rat liver 9000 g supernatant was investigated. Under aerobic conditions, ring oxidation to 6-hydroxy-2-nitropyrene and nitroreduction to 2-aminopyrene (2-AP) were observed. When incubations were carried out in an atmosphere of nitrogen, 2-AP was the only metabolite detected. These results are consistent with those observed with 1-NP. In vitro metabolic activation of 2-NP to DNA adducts catalyzed by xanthine oxidase was also examined. Two adducts were characterized as N-(deoxyguanosin-8-yl)-2-aminopyrene and N-(deoxyadenosin-8-yl)-2-aminopyrene. The presence of deoxyadenosine adduct, which is derived from the nitroreduction pathway, may contribute to the powerful direct-acting mutagenicity of 2-NP.

Animals↗
PubMed1991

Structural characterization of the major adducts formed by reaction of 4,5-epoxy-4,5-dihydro-1-nitropyrene with DNA.

The only available marker of DNA adducts formed from 1-nitropyrene (1-NP) and DNA, N-(deoxyguanosin-8-yl)-1-aminopyrene, is derived from the nitroreduction pathway. Our studies, as well as those of others, have indicated that multiple DNA adducts are formed from 1-NP in vivo and in vitro. Thus the need for additional DNA adduct markers was apparent. Therefore, it was our goal to characterize the DNA adducts formed from 4,5-epoxy-4,5-dihydro-1-nitropyrene, a metabolite of 1-NP. The epoxide was incubated with calf thymus DNA (pH 5.4). The DNA was enzymatically hydrolyzed to deoxyribonucleosides which were analyzed by reverse phase HPLC. Three major peaks were obtained in yields less than 5%. The structural assignment of these adducts was made by comparison of their proton nuclear magnetic resonance spectra with those of cis- and trans-4,5-dihydro-4.5-dihydroxy-1-nitropyrene, and by long range coupling constants, decoupling experiments, D2O exchange, partitions and acid hydrolysis. Two adducts result from trans and one from cis addition of the N2-exocyclic amino group of deoxyguanosine to the C5-benzylic carbon of the epoxide ring. This is the first report that describes the structure of the DNA adducts formed with a ring-oxidized metabolite of 1-NP. On the basis of this finding we suggest that K-region oxides of 1-NP may be responsible for the formation of the putative 1-NP-DNA adducts in vivo.

Chromatography, High Pressure Liquid↗
PubMed1991

Massive hiatal hernia in children.

Ten children had massive hiatal hernias repaired between January 1982 and February 1991. Their clinical presentation, association with other congenital abnormalities, and postoperative complications were different from those seen in adults. Vomiting (n = 7) and anaemia (n = 7) were the most common symptoms, followed by respiratory distress (n = 5), cough (n = 3), and regurgitation (n = 3). Abdominal pain was uncommon. The clinical diagnosis was confirmed in seven cases by barium meal examination. The most common operation was Nissen's fundoplication (n = 7); the hiatus alone was repaired in the remainder. Five patients developed postoperative complications and two died probably as a result of delay in diagnosis and associated malformations.

Child, Preschool↗
PubMedDate not supplied

Metabolism of [14C]benzyl selenocyanate in the F344 rat.

Benzyl selenocyanate (BSC), a synthetic organoselenium compound, has been shown to inhibit chemically induced tumors in several animal model systems. However, it is not known whether BSC or one of its metabolites is responsible for the chemopreventive effect. An initial approach to this question requires the structural elucidation of BSC metabolites in vitro and in vivo. To determine the structures of BSC metabolites in vitro, we studied the metabolism of [14C]BSC using Aroclor-induced rat liver 9000g supernatant. Under these conditions, BSC was partially converted to dibenzyl diselenide (DDS) and phenylmethaneseleninic acid. The metabolism of [14C]BSC (12.5 mg/kg body weight, 8 mCi/mmol, oral administration) in male F344 rats was also studied. Excretion was monitored by measurement of radioactivity as well as by selenium content using atomic absorption spectrophotometry (AAS). The results indicate that urine was the major route of excretion. Approximately 22% of the dose was excreted in the urine over the course of 35 days; however, a large portion (approximately 70%) of the dose remained in the body. Benzoic acid, hippuric acid, and their sulfate and glucuronide conjugates, accounting for 16% of the dose, were identified in the urine. The formation of these metabolites indicates that BSC is metabolized in part via bond cleavage between the benzyl moiety and the selenocyanate function. Additional support for this cleavage was obtained from fecal analysis; over the course of 23 days 9% of the selenium (AAS) but only less than 1% of the radioactivity was recovered in feces. No radioactivity was detected in the exhaled air. We also studied the metabolism of [14C]DDS (17.3 mg/kg body weight, 2.5 mCi/mmol) in male F344 rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗