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E A Smuckler

Publications and source records attributed to E A Smuckler.

At least 37 records · Page 2Linked to original sources
PubMed1985

Liver pathology accompanying chronic liposome administration in mouse.

Particulate drug carriers have a pronounced tendency to localize in the mononuclear phagocyte system and chronic administration of such carriers can result in reticuloendothelial (RE) blockade. In a previous study (Allen et al., J. Pharmacol. Exp. Therap., 229, 267, 1984) we have examined the ability of chronic i.v. administration of liposomes of a variety of compositions to cause RE blockade in mice. In this communication we report on the time course of histological changes in liver accompanying chronic liposome administration in samples collected at the time of our previous studies. The predominant histological feature was the appearance of a granulomatous reaction in liver. Granulomas were frequent in liver tissue of mice receiving 2 or more injections of sphingomyelin:phosphatidylcholine, 4:1 or distearoylphosphatidylcholine:cholesterol, 1:1 liposomes, but disappeared shortly after termination of liposome injections. In mice receiving phosphatidylcholine:cholesterol, 2:1 liposomes no granulomas in liver were apparent during the injection course (10 injections of 2 mg phospholipid each over 25 days) but granulomatous inflammation of the liver became apparent 2 weeks after the last injection and had not resolved by 9 weeks post-injection. The appearance of granulomas was correlated with depression of phagocytic index and their disappearance was correlated with normalization or stimulation of reticuloendothelial function. These observations may be related to the rate of phospholipid metabolism for the various phospholipid types or to the nature of phospholipid metabolites.

Animals↗
PubMed1985

Nitrous oxide does not hinder the repair of halothane-induced hepatic injury in the rat.

Nitrous oxide administration may limit DNA synthesis by inactivating methionine synthetase, and may thus hamper the repair of an injured organ such as the liver. To test this possibility, we pretreated rats with phenobarbital and exposed them to 0.3 MAC halothane in 9% oxygen for 46 min, followed immediately and again 24 hr later by 70% nitrous oxide (0.25 MAC) at an FIO2 of 0.30 for 2 hr. The results from this group were compared with an anesthetic control group in which 0.35% isoflurane (0.25 MAC) was substituted for the nitrous oxide. Additional groups were given a third exposure to nitrous oxide or isoflurane 48 hr after the halothane exposure. All rats were killed 24 hr after their last anesthetic exposure. A second (nonanesthetic) control group of phenobarbital-pretreated rats received 0.3 MAC halothane in 9% oxygen for 46 min and no anesthetic thereafter. They were killed 24, 48, or 72 hr later. Histologic changes in the livers of rats did not differ among the groups given nitrous oxide, isoflurane, or no additional anesthetic after exposure to halothane alone. Thus neither nitrous oxide nor isoflurane appears to hinder the repair of hepatic injury produced by halothane in the hypoxic rat model.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1984

Effects of 1,2-dibromo-3-chloropropane on hepatic heme synthesis.

Previous studies showed that 1,2-dibromo-3-chloropropane (DBCP) caused a decrease in hepatic microsomal cytochrome P-450 [D.E. Moody, B. Head, and E.A. Smuckler (1979) J. Environ. Pathol. Toxicol. 3, 177-190; D.E. Moody, G.A. Clawson, C.H. Woo, and E.A. Smuckler (1982) Toxicol. Appl. Pharmacol. 66, 278-279], suggesting that hepatic heme metabolism may be affected by DBCP treatment. This study tested this hypothesis. Various parameters of hepatic heme synthesis were measured at intervals ranging from 0 to 72 hr in male Sprague-Dawley rats given a single oral dose (200 mg/kg) of DBCP. Incorporation of the radiolabeled heme precursor [delta-14C]aminolevulinic acid (14C-ALA) into liver, protein, extracted heme, and subcellular fractions of liver homogenates was significantly decreased to 75, 58, and 81% of controls, respectively, at 24 hr. At 48 and 72 hr after DBCP treatment, the accumulation of 14C-ALA label after 4 hr in liver homogenates and subcellular fractions was significantly increased in comparison to controls. These changes in 14C-ALA uptake were accompanied by decreases in total liver and microsomal heme, but not mitochondrial heme. Decreases were found in the spectral content of two heme proteins, cytochromes P-450 and b5, and the activity of another heme protein, catalase. Heme oxygenase activity increased to 130, 151, 209, and 186% of control values at 12, 24, 48, and 72 hr after DBCP, respectively. A slight, but significant, increase in ALA-synthetase to 112% of controls occurred at 24 hr, and slight, but significant, decreases in ALA-dehydratase to 90 and 80% of control occurred at 12 and 24 hr, respectively. No significant changes in uroporphyrinogen-1-synthetase or ferrochelatase at the time points tested was noted. The porphyrin content of liver was increased to 130% of control, while the serum and urine porphyrin levels were decreased to 30% of the control values at 24 hr. Liver ALA content was not significantly altered through the time period studied, but serum and urine levels were increased at 24 hr to 176 and 130% of the control values, respectively. In conclusion, the decreases in liver heme proteins following a single oral dose of DBCP are accompanied by alterations in heme turnover, particularly a prolonged increase in heme oxygenase activity.

Aminolevulinic Acid↗
PubMed1984

Autopsy findings in the acquired immune deficiency syndrome.

The medical records, premortem biopsy specimens, and autopsy materials from 36 patients with acquired immune deficiency syndrome (AIDS) were reviewed. The majority of the patients were homosexual men. Widely metastatic Kaposi's sarcoma was seen in eight patients, while tumor was confined to the skin in an additional ten. Four patients had high-grade lymphomas. Thirty-five of the 36 patients had at least one opportunistic infection at some point in the course of their illness. Many patients had multiple infectious agents. The most consistent and striking autopsy finding was a severe depletion of lymphoid tissues. Death in the majority (83%) of the patients was attributable to opportunistic infections affecting most commonly the respiratory tract (64%) and meninges (11%). Three patients (9%) died with widely metastatic Kaposi's sarcoma and secondary hemorrhage.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Photoaffinity labeling of the major nucleosidetriphosphatase of rat liver nuclear envelope.

We employed the photoaffinity probe 8-azido-adenosine 5'-triphosphate (aATP) to identify the nuclear envelope (NE) nucleosidetriphosphatase activity (NTPase) implicated in control of RNA transport. The photoprobe was hydrolyzed at rates comparable to those for ATP, with a Michaelis constant of 0.225 mM. Photolabeling was dependent upon UV irradiation (300-nm max) and was not affected by quercetin. Unlabeled ATP or GTP competed with [32P]aATP in photolabeling experiments, and UTP was a less effective competitor, paralleling the substrate specificity of the NTPase. Incubation of NE with aATP led to a UV, time, and concentration dependent irreversible inactivation of NTPase. The inactivation could be blocked by ATP or GTP. Polyacrylamide gel electrophoresis and autoradiography of photolabeled NE showed selective, UV-dependent labeling of a 46-kDa protein with both [gamma-32P]aATP and [alpha-32P]aATP. This band was not labeled with [gamma-32P]ATP. Since the NE NTPase implicated in RNA transport is modulated by RNA, we examined the effects of RNA on the labeling process. Removal of RNA from the NE preparations (by RNase/DNase digestion) reduced NTPase by 30-40% and eliminated photolabeling of the 46-kDa band. Addition of yeast RNA to such preparations increased NTPase activity to control levels and selectively reinstated photolabeling of the 46-kDa band. These results suggest that the 46-kDa protein represents the major NTPase implicated in RNA transport.

Adenosine Triphosphate↗
PubMed1984

Modulation of RNA transport by polyvinylpyrrolidone.

A number of studies have documented substantial loss of nuclear protein during aqueous nuclear isolation procedures. This loss can, to some extent, be counteracted by addition of impermeable macromolecules like polyvinylpyrrolidone, which prevent nuclear swelling. While nucleic acids appear to be much less susceptible to leakage during isolation, the effects of these additives on RNA release during in vitro incubation have not been examined. Here we show that addition of polyvinylpyrrolidone results in significant decreases in RNA transport; inhibition becomes maximal at 50-75 microM addition.

Animals↗
PubMed1984

Localization of nucleoside triphosphatase activity to the inner nuclear envelope and associated heterochromatin.

Nuclear-envelope nucleoside triphosphatase activity (NTPase), an enzymatic activity thought to participate in RNA transport, was localized in rat liver in situ after brief perfusion with 3% paraformaldehyde. Reaction product was distributed along the nucleoplasmic side of the nuclear envelope (NE) in heterochromatin, was only occasionally found at nuclear pores, and nuclear deposition was selectively blocked by inhibitors of NE NTPase activity. Our results suggest that NTPases, which are active in the NE and which participate in RNA transport, are not specifically associated with nuclear-pore complexes.

Animals↗
PubMed1984

Pleomorphic carcinoma of the gallbladder: case report and ultrastructural study.

Carcinomas of the gallbladder with pleomorphic spindle cell histology are unusual. We report such an occurrence in a 47-year-old male with a neoplasm showing both a mixed squamous and a pleomorphic spindle cell pattern. Ultrastructural studies supported the likelihood that this lesion represented a pleomorphic carcinoma and revealed unique paracrystalline structures intimately associated with tonofilaments. For this reason we believe that this and some other previously diagnosed sarcomas and carcinosarcomas of the gallbladder are in reality poorly differentiated carcinomas of either adeno, squamous, or mixed type. This illustrates the need for critical ultrastructural assay to determine the nature of poorly defined and differentiated neoplastic growths.

Carcinoma↗
PubMed1984

Increased nucleoside triphosphatase activity of rat liver nuclear envelope is associated with hepatocarcinogen exposure.

Altered transport of nuclear RNA sequences is an early response to carcinogens. Nuclear envelopes (NE) were isolated and assayed for nucleoside triphosphatase activity (NTPase), on the premise that this enzymatic activity participates in RNA transport. A common feature of the action of five different carcinogens (thioacetamide, 2-acetylaminofluorene, 3'-methyl-4-dimethylaminoazobenzene, dimethylnitrosamine, and aflatoxin B1), at low doses without significant toxicity, was to increase NE NTPase activity and to increase RNA transport, as assessed by the appearance of rapidly labeled RNA in the cytoplasm and by in vitro assay. The increases in NTPase were specific for the NE fraction, and early toxic effects of higher doses initially masked the increases. The induced increases in NE NTPase were long-lived. In contrast, increases in NE NTPase were observed only during the regenerative phase of CCl4 intoxication; the CCl4-induced increase was short-lived and returned promptly to control levels. These changes in NTPase activity were not associated with parallel changes in phosphorylation/dephosphorylation of NE proteins. Increases in NE NTPase and alterations in RNA transport, without attendant nuclear replication, may relate to altered nuclear RNA restriction. This change in a regulatory phenomenon may make these cells more susceptible to further modification, potentially playing a role in the initiation phase of carcinogenesis.

2-Acetylaminofluorene↗
PubMed1984

Brief periods of hypoxia can produce hepatic injury in rats.

To determine whether brief periods of hypoxia could produce hepatic injury, we pretreated Sprague-Dawley rats with phenobarbital, deprived them of food for 24 hr, and then exposed them to various hypoxic mixtures of nitrogen and oxygen for various lengths of time. Rats exposed to 6% oxygen for 15 or more minutes had centrilobular injury, the severity of which was directly related to the length of exposure (r = 0.71). Extrapolation of these data indicated that no injury would occur if exposures were less than 5 min. Experiments using lower concentrations of oxygen did not reveal hepatic injury, probably because death of the animals occurred before the appearance of detectable injury of the liver. Feeding animals before imposition of hypoxia markedly decreased the risk of hepatic injury. Whether patients who are deprived of food preoperatively and whose liver enzymes are induced incur an increased risk of hepatic injury from brief periods of hypoxia remains to be determined.

Animals↗
PubMed1984

Isoflurane does not prevent hepatic injury produced by halothane in rats.

We speculated that the inhibitory effect of isoflurane on the metabolism of halothane might reduce hepatic injury produced by halothane. To test this hypothesis we pretreated male rats with phenobarbital and 24 hr later exposed them to one of three types of anesthesia. One group of rats was anesthetized with 0.6 MAC isoflurane in 21-25% oxygen for 20 min, followed by exposure to 0.3 MAC isoflurane and 0.3 MAC halothane either in 9% oxygen for 46 min (n = 5) or in 12% oxygen for 60 min (n = 11). A second group of rats received 0.3 MAC halothane in 9% oxygen for either 46 min (n = 12) or in 12% oxygen for 60 min (n = 10). The third group received 0.3 MAC isoflurane in 9% oxygen for either 46 min (n = 12) or for 120 min (n = 8). The rats were killed 24 hr after the exposures and liver slides prepared. Histologic examination revealed that rats treated with isoflurane plus halothane, or with halothane alone showed a significant hepatic injury (P less than 0.005) when compared with those treated with isoflurane. Thus isoflurane failed to protect the liver from halothane-induced injury.

Animals↗
PubMed1984

Nitrous oxide, too, is hepatotoxic in rats.

Anesthetic hepatotoxicity was tested under various conditions of hypoxia in rats pretreated with phenobarbital. Administration of 0.3 MAC halothane or fentanyl in 9% oxygen (fractional concentration of inspired oxygen = 0.09) for 46 min produced centrilobular hepatic injury in all rats (P less than 0.001 vs all other groups). Isoflurane, nitrous oxide, and thiopental at 0.3 MAC did not produce hepatic injury greater than that produced in control rats given 9% oxygen, nor was significant injury produced in control phenobarbital-pretreated rats who breathed 6 or 7.5% oxygen for 46 min. With an inspired oxygen concentration of 7.5%, hepatic injury occurred after exposure to 92.5% nitrous oxide (P less than 0.05), but not after enflurane, isoflurane, or thiopental. When hypoxia associated with 9% oxygen was extended to 2 hr, 91% nitrous oxide produced significant injury (P less than 0.001 compared with the controls), while enflurane, isoflurane, and thiopental did not. These and previous results suggest that all anesthetics can produce liver injury in the hypoxic rat model and that the ranking of hepatotoxicity (most to least) may be halothane, fentanyl, nitrous oxide, enflurane = isoflurane = thiopental.

Animals↗
PubMed1983

Hybridization of poly(A)-containing ribonucleic acid transported in vitro to cyclic deoxyribonucleic acid-cellulose transcribed from cytoplasmic poly(A)-containing ribonucleic acid.

Isolated nuclei have been employed to study nucleocytoplasmic RNA transport in vitro; however, the specificity of the in vitro process remains largely undefined. To examine this specificity we have employed a hybridization technique that allows recovery of undegraded RNA after hybridization under stringent conditions. Cytoplasmic poly(A)-containing RNA was isolated from rat liver and used as a template for synthesis of cDNA-cellulose. Rat liver nuclei were isolated and incubated in vitro, and the released poly(A)-containing RNA was hybridized to the cDNA-cellulose transcribed from authentic cytoplasmic RNA. A significant portion hybridized (18.5 +/- 4.4%), comparable to the portion of homologous cytoplasmic poly(A)-containing RNA that hybridized (20.4 +/- 2.3%), indicating a considerable sequence homology between these populations. Similar results were obtained when cDNA was transcribed from RNA which was transported in vitro in 45S ribonucleoprotein (21.6%). Control nuclear RNA hybridized to a significantly smaller extent (9.1 +/- 2.7%), and the percentage hybridizing decreased markedly under conditions that allowed nuclear RNA processing but not transport (to 4.3 +/- 2.1%), showing that the hybridization was not due to nonspecific leakage of nuclear RNA. This technique should prove valuable for following in vitro processing of specific probes and for enrichment of sequences differentially transported in vitro following acute injury or carcinogen treatment of rats.

Animals↗
PubMed1983

Chemicals, cancer and cancer biology.

Chemicals can cause cancer in humans and animals. Two significant questions are how and how frequently do these neoplasms arise? The first documentation of chemically induced cancer in humans was of the occupationally related "soot wart" in 1775. Since that time various carcinogens have been identified. Some compounds act directly on cell populations, whereas others must be metabolized by a host to produce a "proximate" or "ultimate" carcinogen. Because of the variety in carcinogen structure and the multiplicity of modifications to the cellular macromolecules, a simple explanation for chemical effect is unlikely. Furthermore, true neoplastic growth involves at least two and possibly more steps, some of which are reversible. Evidence suggests that cancer represents an altering of differentiation and that chemical agents may act at the level of DNA or on epigenetic regulatory phenomena. The method for selecting the neoplastic cell from those that are normal is not known. Because we cannot explain the mechanisms for cancer formation or the role of chemicals in the process, prudence is needed in determining the significance of human exposure and in relating this exposure to the risk of neoplastic disease.

Animals↗