摘要:

AbstractIt has long been recognized that periportal and centrilobular regions of the liver lobule differ in their sensitivity to many hepatotoxins. For example, carbon tetrachloride damages centrilobular regions while allyl alcohol damages periportal areas of the liver lobule (1). One determinant of the selective susceptibility of different areas of the liver lobule to chemically induced injury is believed to be the sublobular distribution of enzymes involved in detoxification, or activation to more toxic metabolites (2–4). In addition to sublobular enzyme activity, substrate delivery and the availability of necessary cofactors can influence the zone‐specific toxicity of some chemicals. Furthermore, it has been proposed that oxygen gradient across the liver lobule is an important determinant of zonal hepatotoxicity. Thus, studies regarding the zone‐specific nature of hepatotoxicants require that a variety of complex interrelated metabolic processes be considered, and so far exact mechanisms responsible for zone‐selective hepatotoxicity are not completely und

ISSN:0887-2082    

DOI:10.1002/jbt.2570060102

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractCultured fibroblasts treated with divalent cation ionophore A23187 in the presence of extracellular calcium provide a useful model system for studying mechanisms of cell death associated with elevated intracellular calcium concentrations. Cell death induced by A23187 plus calcium can be conveniently monitored as membrane permeabilization to Trypan blue dye. Because lipids are a major component of cell membranes and play an important role in determining membrane permeability, the present study was initiated to identify changes in cell lipid composition that occur during membrane permeabilization induced by calcium plus A23187. The percent label in each of the major structural lipids in biosynthetically labeled NIH3T3 fibroblasts changed<10% during the time course of membrane permeabilization. During the course of membrane permeabilization there was significantly increased label in lysophosphatidylinositol and lysophosphatidylcholine and reduced label in phosphatidylinositol 4,5‐bisphosphate. The time course of these changes corresponded to that of the arachidonic acid release response stimulated by calcium plus A23187, not to the time course of membrane permeabilization, which occurs later. These observations are consistent with lipid metabolism induced by A23187 plus calcium playing only a possible regulatory or intermediatory role in membrane permeabilization, rather than causing direct permeabilization of the lipid phase of the membran

ISSN:0887-2082    

DOI:10.1002/jbt.2570060103

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractPyrazofurin, a pyrimidine nucleoside analogue with antineoplastic activity, inhibits cell proliferation and DNA synthesis in cells by inhibiting uridine 5′‐phosphate (UMP) synthase. It has been previously shown in concanavalin A (con A)‐stimulated guinea pig lymphocytes (23) that pyrazofurininhibited DNA synthesis could be selectively reversed by exogenous uridine (Urd). In this report, we have examined possible mechanisms for the Urd reversal with experiments that determine the ability of exogenous Urd to (a) interfere with either the intracellular transport of pyrazofurin, or the conversion of pyrazofurin to its intracellularly active form, pyrazofurin‐5′‐phosphate; (b) reverse the pyrazofurin block of [14C]orotic acid incorporation into DNA; and (c) alter the pattern of exogenous [3H]Urd incorporation into DNA‐thymine (DNA‐Thy) and DNA‐cytosine (DNA‐Cyt) during pyrazofurin inhibition of pyrimidine de novo biosynthesis. The results of these experiments showed that Urd reversal does not occur through altered pyrazofurin transport or intracellular conversion to pyrazofurin‐5′‐phosphate, nor does it alter the distribution of [3H]Urd in DNA‐Thy and DNA‐Cyt. Instead, these findings indicate that the primary mechanism for exogenous Urd reversal of pyrazofurin inhibition of DNA synthesis involves the reversal of pyrazofurin inhibition of UMP synthase, thus restoring orotic acid incorporation into lymphocyte DNA through t

ISSN:0887-2082    

DOI:10.1002/jbt.2570060104

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractHigh plasma levels of linoleic acid (18:2) may injure endothelial cells, resulting in decreased barrier function of the vascular endothelium. The effects of linoleic acid on endothelial barrier function (transendothelial movement of albumin), membrane‐bound enzyme activities, and possible autooxidation of linoleic acid under experimental conditions were studied. The exposure of endothelial monolayers to 18:2 for 24 hr at 60, 90, and 120 μM. fatty acid concentrations caused a significant increase in transendothelial movement of albumin, with maximum albumin transfer at 90 μM. Fatty acid treatment resulted in the increased appearance of cytosolic lipid droplets. Activities of the membrane‐bound enzymes, angiotensin‐converting enzyme (ACE), and Ca2+‐ATPase increased steadily with increasing time of cell exposure to 90 μM 18:2, reaching significance at 24 hr. Treatment of endothelial cultures with up to 120 μM 18:2 did not cause cytotoxicity, as evidenced by a nonsignificant change in cellular release of [3H]‐adenine. Incubation of 18:2‐supplemented serum‐containing culture media with 1000 μM 18:2 at 37°C for up to 48 hr did not result in formation of autooxidation products. These results suggest that 18:2 itself, and not its oxidation products, plays a major role in disrupting endotheli

ISSN:0887-2082    

DOI:10.1002/jbt.2570060105

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractBenzanthrone, an anthraquinone dye intermediate, is commonly used for the synthesis of a number of polycyclic vat and disperse dyes. Our prior studies have shown that benzanthrone can be metabolized by rat hepatic microsomal cytochrome P450 (P450) (Biochem. Int., 18, 1989, 1237). In this study, the interaction of benzanthrone with rat hepatic microsomal P‐450 and its effect on xenobiotic metabolism have been investigated. Parenteral administration of benzanthrone (40 mg/kg body weight) for 3, 7, or 21 days caused no change in the relative body weight or organ weight of rats. The levels of P450 were found to be reduced (33%‐50%) in all the benzanthrone‐exposed animals at all the time periods. In vitro addition of benzanthrone caused a spectral change with oxidized P450 and concentration‐dependent reduction in the carbon monoxide spectrum of dithionite‐reduced P450. The addition of benzanthrone to hepatic microsomes prepared from phenobarbital‐treated rats resulted in spectral changes characterized by an absorbance maximum at 397 nm indicative of type I binding. In vitro addition of benzanthrone showed a concentration‐dependent inhibition of hepatic aminopyrineN‐demethylase (APD) and ethoxyresorufin‐O‐deethylase (ERD) activities with respective I50values of 9.5 × 10−4and 8.0 × 10−5M. However, the inhibition of aryl hydrocarbon hydroxylase (AHH) even at the highest concentration of benzanthrone (10−2M), was of the order of only 29%. In vivo administration of benzanthrone also led to the inhibition of APD, AHH, and ERD activities at all treatment times although the magnitude of inhibition was of a lower order. Benzanthrone treatments caused significant depletion of glutathione content with a concomitant enhancement of lipid peroxidation. Also, benzanthrone resulted in a significant inhibition of the cytosolic enzyme, GSH‐transferase (23%–34%), although the other enzyme, quinone reductase, which helps in the removal of toxic quinones, was found to be elevated (184%–199%). These results suggest several mechanisms by which benzanthrone may inhibit P450. This impairment of xenobiotic metabolism as well as the enhancement of lipid peroxidation may be relevant to the observed symptoms of be

ISSN:0887-2082    

DOI:10.1002/jbt.2570060106

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractThe sublethal biochemical effects of pentachlorophenol (PCP) were investigated in live, intact red abalones (Haliotis rufescens), using a flow‐through exposure system, by in vivo31P NMR spectroscopy. Based on rangefinding tests (6‐hr LC50= 1.6 mg/L; 6‐hr no‐observable‐effect‐level (NOEL) = 0.8 mg/L), three abalones were separately exposed to a sublethal concentration (1.2 mg/L) for 5 hr, followed by a 13 hr recovery period. Effects in foot muscle included both a decrease in phosphoarginine and an increase in inorganic monophosphate concentrations ([PA] and [Pi], respectively); both foot muscle concentrations of adenosine triphosphate [ATP]and intracellular pH (pHi) also declined. Parallel in vitro experiments revealed that concentrations of glycerol 3‐phosphate, lactate, citrate, succinate, malate, and alanine (Ala) all increased, while those of glyceraldehyde 3‐phosphate and glutamine (Gln) remained stable. Also, these effects were not evident until 2 hr into exposure, possibly the time required for PCP to attain an effective concentration in foot muscle. During recovery, while Pideclined to pre‐exposure levels, [PA] completely recovered in only one individual. Also, realkalinization of pHiwas similar to recovery of [Pi], and ATP returned to near‐initial levels, as did glycerol 3‐phosphate, lactate, succinate, malate, and Ala; glyceraldehyde 3‐phosphate, citrate, and Gln levels declined. Recovery responses corresponded to the time for PCP clearance from foot muscle. The effects of PCP were similar to those of hypoxia, fatigue, hypersalinity, and arginine kinase inhibitors, and so sublethal PCP concentrations may also inhibit electron transport and arginine kinase as well as uncouple mitochondrial oxidative phosphorylation in intact molluscs. Thus, the effects of pollutants on key biochemical processes may now be measured in intact aquatic organisms as they occur, improving our ability to accurately assess the environmental effects of pollu

ISSN:0887-2082    

DOI:10.1002/jbt.2570060107

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractLantadene A (22 β‐angeloyloxy‐3‐oxoolean‐12‐en‐28‐oic acid), a pentacyclic triterpenoid compound from lantana (Lantana camara) leaves has been obtained in two polymorphic forms I and II. Form I had white, fluffy, and rod‐shaped uniform crystals. Form II particles were irregular, shining, and polyhedral. The two forms differed in melting behavior. The powder x‐ray diffraction of form I showed sharp peaks whereas form II did not contain distinct peaks. From single‐crystal three‐dimensional x‐ray structure determination, the molecular structure of form I has been established. A/B and B/C rings of the molecule are trans fused while D/E rings are cis fused. The packing of the molecule is stabilized by hydrogen bonding. Form I of lantadene A was nontoxic to guinea pigs on oral administration. Form II induced ictericity and toxicity associated with decrease in feed intake and fecal output, hepatomegaly, increase in plasma bilirubin, and a

ISSN:0887-2082    

DOI:10.1002/jbt.2570060108

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractThe results of kinetic experiments measuring the effects of a variety of ligands on the sulfur‐cyanolysis reaction catalyzed by serum albumin point to the conclusion that the active site for cyanolysis is on subdomain 3‐AB. Relationships among the inhibition by short‐chain fatty acids, the activation byp‐nitrophenyl acetate, and the influence of bilirubin and L‐tryptophan on these effects indicate that the cyanolysis active site and the known primary binding site for indoles are both near, but on opposite sides of, tyrosine‐409 of bovine albumin (tyrosine‐411 of h

ISSN:0887-2082    

DOI:10.1002/jbt.2570060109

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

摘要:

AbstractWe have studied the effects of diethyldithiocarbamate (DDTC) on the biotransformations of toxic doses of tetrachloro (d,l‐trans)1,2‐diaminocyclohexaneplatinum(IV) (tetraplatin) in Fischer 344 rats. In animals not treated with DDTC, tetraplatin was rapidly converted to dichloro(d,I‐trans)1,2‐diaminocyclohexaneplatinum(II) [PtCl2(dach]. Subsequent biotransformations included the transient formation of the (d,I‐trans)1,2‐diaminocyclohexane‐aquachloroplatinum(II) [Pt(H2O)(Cl)(dach)]+ complex, followed by formation of the platinum (Pt)‐methionine and either Pt‐cysteine or Pt‐ornithine complexes. Significant amounts of free (d,I‐trans) 1,2‐diaminocyclohexane (dach) were observed in plasma as a result of intracellular trans‐labilization reactions. DDTC caused a marked decrease in both total and protein‐bound platinum in the circulation. A significant increase in the plasma concentration of free dach was also observed as a result of formation of the Pt(DDTC)2complex. Some of the free dach could have arisen from intracellular reactions with DDTC, but the displacement of platinum from plasma proteins was more than sufficient to account for the increase in free dach in the circulation. DDTC treatment also decreased plasma concentrations of tetraplatin, PtCl2(dach), [Pt(H2O)(Cl)(dach)]+, the Pt‐methionine complex, and one unidentified biotransformation product, but had no effect on the Pt‐cysteine (or Pt‐ornithine) complex. These effects of DDTC on protein‐bound platinum and low‐molecular‐weight biotransformation products in plasma may contribute to the decrease in tetrapl

ISSN:0887-2082    

DOI:10.1002/jbt.2570060110

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY

ISSN:0887-2082    

DOI:10.1002/jbt.2570060111

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1991

数据来源: WILEY