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PubMedDate not supplied

Influence of aging on the acute depletion of reduced glutathione induced by electrophilic agents.

A severe age-dependent depletion of reduced glutathione (GSH) occurs in rat forebrain at 1-3 h from intraperitoneal injection of the electrophilic agents cyclohexene-1-one and cycloheptene-1-one. Chronic pretreatment with central dopamine agonists (i.e., ergot alkaloids; particularly, dihydroergocriptine) partially counteracts the GSH depletion induced in 15-month-old forebrains by the prooxidants tested. In contrast, chronic pretreatment with a vasodilator agent (i.e., papaverine) magnifies the GSH depletion.

Aging↗
PubMed1983

The role of 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone (BHT quinone methide) in the metabolism of butylated hydroxytoluene.

Male rats were fed 5.45 mmol/100 g diet butylated hydroxytoluene (BHT) or 2,6-di-tert-butyl-4-hydroxymethylphenol (BHT alcohol) in either a standard or purified diet for 1 wk, after which their livers were analysed for levels of unconjugated BHT metabolites and their blood clotting times were assayed. The BHT quinone methide, 2,6-di-tert-butyl-4-methylene-2,5-cyclohexadienone, was only found in appreciable concentrations (6-9 micrograms/g liver) in the livers of rats given BHT. For rats fed the purified diet, BHT and BHT alcohol caused significant reductions of the prothrombin index to 23 and 70%, respectively, of the control value, though rats fed the standard diet were not similarly affected. Liver concentrations of BHT in rats fed BHT alcohol also varied according to diet, indicating that the metabolic pathway may be affected by diet. Biliary excretion of the quinone methide was observed in rats given 140 mg BHT alcohol ip.

Animals↗
PubMed1994

The effect of colupulone (a HOPS beta-acid) on hepatic cytochrome P-450 enzymatic activity in the rat.

Colupulone, a component of hops, was examined for its ability to alter rat hepatic cytochrome P-450 enzymatic activity, expression of hepatic cytochrome P-450 mRNA, and in vitro promutagen activation. Colupulone was fed to male Sprague-Dawley rats for 5 days at 0.36% in the modified AIN 76 diet. Three cytochrome P-450 enzymatic activities were measured, and the corresponding steady-state mRNA levels were examined by Northern blot hybridization. Colupulone increased cytochrome P450IIB and P450IIIA steady-state mRNA levels. In vitro promutagen activation was measured in the Ames assay using liver homogenates from each treatment group. Colupulone treatment did not alter the ex vivo cytochrome P-450-mediated activation of aflatoxin B1 or benzo[a]pyrene to their mutagenic forms. The effect of long-term colupulone administration on in vivo cytochrome P-450 enzymatic activity remains to be determined.

Administration, Oral↗
PubMed1986

Toxicology and carcinogenesis studies of isophorone in F344 rats and B6C3F1 mice.

Toxicology and carcinogenesis studies of isophorone were conducted by administering 0, 250, or 500 mg/kg body weight per day by gavage in corn oil to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days/week, for 103 weeks. Dosed male rats developed proliferative lesions of the kidney including hyperplasia, adenoma, and adenocarcinoma of the renal tubule, and epithelial hyperplasia of the renal pelvis. Non-proliferative kidney lesions observed in dosed male rats included mineralization, and a more severe nephropathy in low dose animals than in controls or high dose animals. Carcinomas of the preputial gland occurred in high dose male rats. No isophorone-related lesions were observed in female rats. In male mice, isophorone exposure may have been associated with an increase in hepatocellular neoplasms and mesenchymal neoplasms of the integumentum in high dose animals, and with a marginally increased incidence of lymphoma in low dose male mice. In mice, no non-neoplastic lesions in males or females, or neoplastic lesions in females were considered associated with isophorone administration.

Administration, Oral↗
PubMed1992

Differences in alpha 2u-globulins increased in male rat kidneys following treatment with several alpha 2u-globulin accumulating agents: cystein protease(s) play(s) an important role in production of kidney-type-alpha 2u-globulin.

Effects of alpha 2u-globulin accumulating agents on alpha 2u-globulins in rat kidneys were examined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting analysis. Treatment of male animals with decalin (150 mg/kg), 2,2,4-trimethylpentane (50 mg/kg), isophorone (150 mg/kg), d-limonene (150 mg/kg) or 1,4-dichlorobenzene (150 mg/kg) by gavage for 14 consecutive days in each case resulted in a marked intensification of a protein band corresponding to kidney-type-alpha 2u-globulin, with a molecular mass calculated to be approximately 16 kDa. However, intraperitoneal treatment with leupeptin and E-64 (two times 0.07 mmol/kg, for each), well known cystein protease inhibitors, while only slightly increasing this kidney-type-alpha 2u-globulin band, caused the intensification of a approximately 19-kDa molecular mass protein band which was revealed to be a native-type-alpha 2u-globulin by SDS-PAGE and immunoblotting. These results indicated that at least two types of alpha 2u-globulin can be increased in male rat kidney by chemical treatment. Moreover, cystein protease(s) appear(s) to play an important role in the degradation of alpha 2u-globulin and particularly in the conversion of native-type-alpha 2u-globulin to kidney-type-alpha 2u-globulin in rat kidneys.

Alpha-Globulins↗
PubMed1993

Effects of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethylphenyl) cyclohex-2-enone on hepatic haem biosynthesis: species differences in hepatic porphyria.

2-[1-(Ethoxyimino)propyl]-3-hydroxy-5-(2,4,6-trimethylphenyl) cyclohex-2-enone (ETC) is a novel alkyl ketone herbicide. Continuous administration of ETC to mice for 28 days resulted in marked liver enlargement and severe intrahepatic cholestasis. These effects have been shown to result directly from a rapid and marked accumulation of porphyrin in the liver. The porphyrin which accumulates in the liver has been identified as protoporphyrin IX and dose response and time course studies confirm prior inhibition of mitochondrial ferrochelatase as the causal lesion. ETC was a very potent porphyrinogenic compound in mice, with a no-effect level for a single oral dose of 1 mg/kg. Rats and hamsters were insensitive to this type of hepatotoxicity following single oral doses of up to 750 mg/kg or following repeated, and indeed prolonged administration. The sensitivity of different species to ETC-induced porphyria correlated with the effect of ETC on hepatic ferrochelatase activity. The inhibition of ferrochelatase activity and the hepatic porphyria in mice were both found to be readily reversible upon withdrawal of ETC.

Administration, Oral↗
PubMed1990

Key role of diacylglycerol-mediated 12-lipoxygenase product formation in angiotensin II-induced aldosterone synthesis.

We have shown earlier that the 12-lipoxygenase product of arachidonic acid (AA), 12-hydroxyeicosatetraenoic acid (12-HETE), plays an important role in mediating angiotensin II (AII)-induced aldosterone secretion (J. Clin. Invest. (1987) 80, 1763). In the present study, we have evaluated whether diacylglycerol (DG) is the source of arachidonic acid giving rise to this 12-HETE. Treatment of rat adrenal glomerulosa cells with a DG lipase inhibitor, RHC 80267, which prevents conversion of DG to AA and HETEs, blocked AII-induced aldosterone and 12-HETE formation. In contrast, a DG kinase inhibitor, R59022, which prevents conversion of DG to phosphatidic acid, potentiated AII-induced aldosterone and 12-HETE formation. These two inhibitors block DG metabolism which would be expected to lead to increased DG levels and protein kinase C activity and AII-induced steroidogenesis. However, only R59022 potentiated AII action while RHC 80267 was inhibitory. This suggests that conversion of DG to AA and 12-HETE is important for AII action. Further proof for this was obtained by measuring [3H]AA-labeled DG levels. The combination of the inhibitors significantly potentiated AII-induced DG formation even though this same combination was inhibitory on AII-induced aldosterone and 12-HETE. Thus, the inhibitory effect of RHC 80267 is due to blockade of AA release and not of DG formation. These results suggest that DG plays a dual role in AII action, both as an activator of protein kinase C and as a source of AA for 12-HETE formation.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1993

Differential involvement of phospholipase A2 in phorbol ester-induced luteinizing hormone and growth hormone release from rat anterior pituitary tissue.

The protein kinase C (PKC) activator, phorbol 12,13-dibutyrate (PDBu) induced the release of both luteinizing hormone (LH) and growth hormone (GH) from proestrous rat anterior pituitary pieces in vitro. Phorbol 12,13-dibutyrate-induced LH, but not GH release was readily inhibited by the phospholipase A2 (PLA2) inhibitors, quinacrine, aristolochic acid, ONO-RS-082 and chloracysine. Furthermore, PDBu induced release of [3H]arachidonic acid ([3H]AA) from pre-labelled anterior pituitary tissue that was prevented in the presence of quinacrine, aristolochic acid and ONO-RS-082 but not the diglyceride lipase inhibitor RHC 80267. The effect of PDBu was completely inhibited by staurosporine and the selective PKC inhibitor Ro 31-8220 but only partially by low concentrations of H7; consistent with the involvement of both H7-sensitive and H7-resistant forms of PKC in the activation of PLA2 by PDBu. The protein synthesis inhibitor cycloheximide inhibited the release of both [3H]AA and LH that had been induced by PDBu, whereas LH release induced by the PLA2 activator mellitin was cycloheximide-insensitive. These results suggest that PKC activators may induce LH but not GH release from anterior pituitary tissue by a mechanism involving activation of a PLA2, brought about by a process which is reliant on protein synthesis.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1985

Evidence for arginine residues in the immunoglobulin-binding sites of human Clq.

The immune complex binding activity of human Clq was lost following treatment of the protein with the arginine-selective reagents cyclohexane 1,2-dione and phenylglyoxal. Both inactivations followed pseudo-first-order kinetics. The affinity of Clq for immune complexes was reduced 7-fold following cyclohexane-1,2-dione treatment, and could be substantially restored by treatment of the modified protein with hydroxylamine. Heat-aggregated IgG protected Clq against inactivation by both reagents. Incorporation of 25 molecules of [7-14C]phenylglyoxal per Clq molecule completely inactivated the protein. These data are consistent with the presence of arginyl residues in the immunoglobulin recognition sites of human Clq.

Antigen-Antibody Complex↗
PubMed1983

Metabolism of glycerate-2,3-P2-III. Arginine-specific reagents inactivate the phosphoglycerate mutase, glycerate-2,3-P2 synthase and glycerate-2,3-P2 phosphatase activities of rabbit muscle phosphoglycerate mutase.

Treatment of rabbit muscle phosphoglycerate mutase with diketones (2,3-butanedione and 1,2-cyclohexanedione) and with glyoxal derivatives (methylglyoxal and phenylglyoxal) produces the loss of the three activities of the enzyme: phosphoglycerate mutase, glycerate-2,3-P2 synthase and glycerate-2,3-P2 phosphatase. Hydroxylamine reactivates all the activities of the modified enzyme. Inactivated phosphoglycerate mutase is unable to form the functionally active phosphoenzyme when mixed with glycerate-2,3-P2. Both substrate and cofactor protect against inactivation. These results provide additional evidence of the intrinsic character of the three enzymatic activities of phosphoglycerate mutase and favor their location at the same active site. In addition, they suggest that arginine is involved in the binding of the cofactor to the enzyme.

Animals↗
PubMed1991

A new cyclitol derivative influences inositol metabolism in Neurospora crassa.

Cyclitol derivatives have been synthesized and screened for growth inhibitory effect upon prokaryotic and eukaryotic organisms. One derivative, (2S,3R,5R)-3-azido-2-benzoyloxy-5-hydroxycyclohexanone, was studied in detail: it has no effect upon bacteria, but it is inhibitory to Neurospora crassa. In Neurospora crassa it increased the amount of myo-inositol-1-phosphate synthase and inhibited the activity of myo-inositol-monophosphatase. The enhanced synthesis of myo-inositol-1-phosphate synthase was the consequence of lowering the intracellular inositol concentration. Li+ treatment of Neurospora crassa has effects similar to those of P.I.-658.

Cell Division↗
PubMed1995

Determination of semicarbazide-sensitive amine oxidase activity in human plasma by high-performance liquid chromatography with fluorimetric detection.

We report here a simple and sensitive method for the measurement of semicarbazide-sensitive amine oxidase (SSAO) activity in human plasma. Benzaldehyde, generated during a 1-h incubation of plasma with benzylamine, is derivatized with the specific aldehyde reagent dimedone after prior deproteinization. Quantitation of the derivatization product is done by automated injection onto an isocratic high-performance liquid chromatographic system with fluorimetric detection. The assay shows good linearity and reproducibility (intra-assay C.V. 7%). Detection limit is 25 mU/l (= pmol/ml/min). In 51 healthy controls (age 49 +/- 13 yr, 20 males) the measured SSAO activity was 352 +/- 102 mU/l (mean +/- S.D.). A large number of samples (70-80) can easily be processed in one day by one technician.

Adult↗
PubMed1993

Measurement of n-alkanals and hydroxyalkenals in biological samples.

A modified method was developed to measure nM levels of a range of n-alkanals and hydroxyalkenals in biological samples such as blood plasma and tissue homogenates and also in Folch lipid extracts of these samples. Butylated hydroxytoluene (BHT) and desferrioxamine (Desferal) were added to samples to prevent artifactual peroxidation. Aldehydes were reacted with 1,3-cyclohexanedione (CHD), cleaned up by solid-phase extraction on a Sep-Pak C18 cartridge and the fluorescent decahydroacridine derivatives resolved by reverse-phase high-performance liquid chromatography (HPLC) with gradient elution. A wider range of aldehydes was detected in lipid extracts of plasma and liver homogenate compared to whole (unextracted) samples. Human plasma contained nM levels of acetaldehyde, propanal, butanal, pentanal, hexanal, and heptanal. 4-Hydroxynonenal (0.93 nmol/g) and alkanals with two to six carbons (up to 7.36 nmol/g) were detected in rat liver. Recovery of aldehydes added to whole plasma or to lipid extracts of plasma was dependent on carbon chain length, varying from 95% for acetaldehyde to 8% for decanal. Recovery from biological samples was significantly less than that of standards taken through the Sep-Pak clean-up procedure, suggesting that aldehydes can bind to plasma protein and lipid components.

Aldehydes↗
PubMed1994

Antioxidant properties of Ambroxol.

We tested whether Ambroxol, a drug which stimulates the release of surfactant by pneumocytes type II, may also possess antioxidant properties. To assess the reactivity of Ambroxol with reactive oxygen species, we analysed its ability to decompose hydrogen peroxide (H2O2) and to inhibit the superoxide (O2.-)-dependent autooxidation of pyrogallol, hydroxyl radical (.OH)-mediated deoxyribose oxidation, and hypochlorous acid (HClO-induced chlorination of monochlorodimedon. Ambroxol was found to be a sufficient scavenger of HClO and .OH and also revealed the capacity to decompose H2O2. At concentrations of 25 and 70 microM, it inhibited HClO-induced chlorination of monochlorodimedon by 22 +/- 13 and 59 +/- 14%, respectively. Similarly, at concentrations of 1, 2, and 10 mM, Ambroxol decreased .OH-mediated deoxyribose oxidation by 47 +/- 11, 75 +/- 9, and 89 +/- 4%. In addition, at concentrations of 1 to 5 mM, it completely protected linoleic acid from .OH-induced peroxidative damage. Ambroxol had a weak effect on O2.(-)-dependent autooxidation of pyrogallol. Our results indicate that Ambroxol has antioxidant activity, which may have clinical significance in protecting lung tissue from oxidant-induced injury.

Ambroxol↗
PubMed1996

Mechanism of tetrahydroxy-1,4-quinone cytotoxicity: involvement of CA2+ and H2O2 in the impairment of DNA replication and mitochondrial function.

In this work we investigated the toxicity of a polyphenolic p-benzoquinone derivative, the tetrahydroxy-1,4-quinone (THQ) toward V79 Chinese hamster fibroblasts and analyzed the role of H2O2 and Ca2+ in that mechanism. The exposure of exponentially growing cultures to THQ, in the presence of 1.0 mM Ca2+, caused a dose-dependent inhibition of cell growth and DNA synthesis. Complete prevention of those effects by catalase indicated that H2O2-induced damages should underlie both toxic processes. Further detection of a rise in the intracellular free Ca2+ concentration ([Ca2+]i) in cells exposed to THQ plus Ca2+, together with the partial protection conferred by the intracellular Ca(2+)-chelator fura-2 against cell growth inhibition, indicated that a disruption of Ca2+ homeostasis is a determinant event in THQ cytotoxicity. Furthermore, the intracellular accumulation of rhodizonic acid (RDZ), the primary oxidative product of THQ, indicated that THQ, or its corresponding semiquinone form, was entering the cells and undergoing further autoxidation to RDZ. It was also evidenced that mitochondria represent an important target in the development of THQ toxicity, as shown by the disruption of the transmembrane electrical potential (delta psi) of isolated rat liver mitochondria, as well as by the Ca(2+)-release by mitochondria of permeabilized V79 cells. We concluded that disruption of Ca2+ homeostasis and generation of H2O2 are critically involved in THQ-induced impairment of DNA replication and mitochondrial functions, leading ultimately to cell growth inhibition.

Animals↗
PubMed1993

Interleukin-1 selectively potentiates bradykinin-stimulated arachidonic acid release from human synovial fibroblasts.

Exposure of human synovial fibroblasts prelabelled with [3H]arachidonic acid to bradykinin causes a rapid and sustained increase in arachidonic acid release, a transient increase in cytosolic calcium and an increase in radiolabelled diacylglycerol. Activation of arachidonic acid release by bradykinin was potentiated by interleukin-1 added either simultaneously with bradykinin or to cultures 24 h before addition of bradykinin. In contrast, interleukin-1 did not modify bradykinin-induced increases in cytosolic calcium or diacylglycerol. The stimulation of arachidonic acid release in response to bradykinin, in the absence or presence of interleukin-1, was not affected by RHC-80267, an inhibitor of diacylglycerol kinase, suggesting that deacylation of diacylglycerol was not an important pathway of arachidonic acid production in cultures exposed to bradykinin. This conclusion is supported by the observation that increased release of arachidonic acid was not accompanied by increased release of [14C]stearic acid in cultures labelled with both isotopes. Bradykinin-stimulated release of arachidonic acid was prevented by down-regulating protein kinase C by pretreatment with phorbol 12-myristate 13-acetate and was unaffected by inhibitors of protein synthesis actinomycin D or cycloheximide. On the other hand, interleukin-1 amplification of bradykinin-stimulated release of arachidonic acid was blocked by actinomycin D and cycloheximide. The results from this study point to activation of phospholipase A2 as the source of arachidonic acid in response to bradykinin. Our data further indicate that interleukin-1 selectively potentiates bradykinin activation of a phospholipase A2 by a mechanism requiring protein synthesis, but has no effect on bradykinin activation of phospholipase C.

Arachidonic Acid↗
PubMed1995

Effect of the diglyceride lipase inhibitor, RG80267, on epithelial chloride secretion induced by various agents.

We previously reported that a diglyceride lipase inhibitor, RG80267, inhibits chloride secretion stimulated by adenosine agonists, stimuli whose effects appear unrelated to cAMP, cGMP or cytosolic calcium. Here, the effect of RG80267 on Cl- secretory responses to agents which do utilize these messengers was examined. RG80267 inhibited responses to vasoactive intestinal polypeptide, forskolin (cAMP-dependent) and E. coli heat stable enterotoxin (cGMP-dependent), but not to prostaglandin E1 or cholera toxin (cAMP-dependent). RG80267 enhanced responses to histamine (calcium-dependent). The inhibitory effect of RG80267 was not due to inhibition of cAMP accumulation. Arachidonic acid release may participate in chloride secretion. Vasoactive intestinal polypeptide, but not prostaglandin E1, released radiolabel from cells preloaded with [3H]arachidonic acid. There may thus be differences between mechanisms of various cyclic nucleotide-dependent chloride secretory responses. Arachidonic acid release may modulate the extent of secretion elicited by some secretagogues.

Alprostadil↗