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PubMed1986

Propylthiouracil inducible glutathione transferases. Selective induction of ligandin (glutathione transferase 1-1).

Repeated administration of propylthiouracil (PTU) resulted in an increase in glutathione (GSH) transferases activity in rat liver cytosol toward various substrates except for epoxy(p-nitrophenoxy)propane. The enzyme from rat treated with PTU showed high activity with 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid. GSH transferases were separated into five forms by CM-Sephadex C-50 column chromatography to detect which isozymes were induced by PTU treatment. Although the activity of the unretained fraction obtained from the column was slightly increased by PTU treatment, the treatment markedly elevated the activity of GSH transferase 1-1. On the other hand, the activities of GSH transferases 1-2, 3-3 and 2-2 were little changed. In addition, an analysis of GSH transferase 1-1 from CM-Sephadex C-50 using SDS-PAGE confirmed that it comprised the 1-1 homodimer. This fraction was then further purified by passing it through a hydroxylapatite column and the partially purified GSH transferase 1-1 from rats treated with PTU was found to have the same characteristics as the control, e.g. the same Km values for GSH and CDNB and the same substrate spectrum. It was concluded that PTU specifically induced GSH transferase 1-1 among the cationic transferases.

Animals↗
PubMed1989

Glutathione S-transferases and glutathione peroxidases in doxorubicin-resistant murine leukemic P388 cells.

Energy-dependent rapid drug efflux is believed to be a major factor in cellular resistance to doxorubicin (DOX). However, several recent studies have demonstrated that cellular DOX retention alone does not always correlate with its cytotoxicity and suggest that mechanisms other than rapid drug efflux may also be important. In the present study, we have compared glutathione (GSH) S-transferase (GST), selenium-dependent GSH peroxidase and selenium-independent GSH peroxidase II activities in DOX-sensitive (P388/S) and resistant (P388/R) mouse leukemic cells. The GST activity towards 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid (EA) was markedly higher in P388/R cells compared to P388/S cells. Purification of GST by GSH-affinity chromatography from an equal number of P388/S and P388/R cells revealed an increased amount of GST protein in P388/R cells. Immunological studies indicated that alpha and pi type GST isoenzymes were 1.27- and 2.2-fold higher, respectively, in P388/R cells compared to P388/S cells. Selenium-dependent GSH peroxidase activity was similar in both the cell lines, whereas selenium-independent GSH peroxidase II activity was approximately 1.36-fold higher in P388/R cells compared to P388/S cells. These results suggest that increased GSH peroxidase II activity in P388/R cells may contribute to cellular DOX resistance by enhancing free radical detoxification in this cell line.

Animals↗
PubMed1989

Electrophoretic and immunological analysis of glutathione transferase isoenzymes of human kidney carcinoma.

By sequential use of GSH-affinity chromatography and chromatofocusing, the isoenzymes of glutathione transferase from tumor and non-tumor kidney tissues have been purified and their properties compared. On the basis of electrophoretic mobilities on SDS/polyacrylamide gel, substrate specificities toward the diagnostic substrates cumene hydroperoxide and ethacrynic acid and immunoreactivity with antisera raised against alpha, mu and pi class glutathione transferases, it was found that most of the isoenzymes purified from both tumor and non-tumor kidney can be identified as members of either alpha or pi classes. All the samples investigated lacked mu class glutathione transferase. In addition, we could identify in tumor samples two transferases GST-7.6 and GST-5.8/5.9 which on the basis of immunological properties cannot be related to any of the members of the three major classes of glutathione transferases. The latter do not appear to have corresponding forms in non-tumor tissues. It was suggested that specific transferases can be selectively expressed by tumor kidney carcinoma.

Carcinoma, Renal Cell↗
PubMed1992

Chronic physical activity: hepatic hypertrophy and increased total biotransformation enzyme activity.

Does chronic voluntary physical activity alter hepatic or intestinal capacities for xenobiotic biotransformation? This question was investigated by comparing biotransformation enzyme activities in liver and small intestine of active and sedentary rats. Male rats allowed unlimited access to a running wheel and fed ad lib. for 6 weeks were weight-matched to sedentary controls; the active rats ate 22% more food than the sedentary rats (P less than 0.05). Active rats ran 2.8 +/- 0.6 miles/day. Liver weights were higher in the active rats (11.2 +/- 0.2 vs 9.8 +/- 0.2 g; P less than 0.05), as were total liver protein, and liver microsomal and cytosolic protein (P less than 0.05). As a result of liver hypertrophy, the active rats showed higher total liver activity of several biotransformation enzymes, including 2-naphthol sulfotransferase, styrene oxide hydrolase, benzphetamine N-demethylase, ethacrynic acid glutathione S-transferase and morphine UDP-glucuronosyltransferase (P less than 0.05). In contrast, there was no detectable difference in total liver N-acetyltransferase activity toward p-aminobenzoic acid, 2-naphthylamine, and 2-amino-fluorene as well as, relative hepatic enzyme activity (expressed per g liver or per mg protein) and total and relative intestinal enzyme activity. We conclude that chronic voluntary physical activity, accompanied by an increased food intake, results in liver hypertrophy and potentially increases total hepatic capacity to biotransform certain xenobiotic chemicals.

Animals↗
PubMed1992

Glutathione S-transferase-dependent conjugation of leukotriene A4-methyl ester to leukotriene C4-methyl ester in mammalian skin.

The glutathione S-transferase (GST)-dependent conjugation of reduced glutathione (GSH) with leukotriene A4 (LTA4)-methyl ester in rodent and human skin was investigated. Incubation of [3H]LTA4-methyl ester (1 nmole, approximately 200,000 dpm) with cytosol prepared from rat, mouse and human skin or with affinity purified GST from rat skin cytosol in the presence of GSH resulted in the formation of LTC4-methyl ester. Maximum enzyme activity was observed in rat skin followed by mouse and human skin. With heat-denatured cytosol or in the absence of GSH, the product formation was negligible. GST purified from rat skin cytosol by GSH-agarose affinity chromatography exhibited a several-fold increase in the specific activity of enzyme with 1-chloro-2,4-dinitrobenzene (55-fold), ethacrynic acid (67-fold) and LTA4-methyl ester (12-fold) as substrates. Western blot analysis of the affinity purified GST indicated a predominant expression of the Pi class of GST isozyme followed by Mu and Alpha classes of isozymes. The formation of LTC4-methyl ester was established by its radioactivity profile on high pressure liquid chromatography and absorption spectroscopy. These results suggest that, in addition to xenobiotic metabolism, cutaneous GSTs may also be capable of metabolizing physiological substrates such as LTA4.

Animals↗
PubMed1992

Induction of glutathione S-transferase isoenzymes in mouse liver by 5-(2-pyrazynl)-4-methyl-1,2-dithiole-3-thione (oltipraz).

Treatment of mice with a single dose of oltipraz (OPZ) at 200 mg/kg led to a significant (P less than 0.05) increase in hepatic cytosolic glutathione S-transferase (GST) activity and content. GST activity monitored with 1,2-dichloro-4-nitrobenzene was increased 3.8-fold 3 days after treatment, suggesting the induction of mu class isoenzymes. Ethacrynic acid, a marker for pi class isoforms, showed only a slight increase in GST activity while no induction was observed with cumene hydroperoxide, an indicator for the alpha class. The increase in mu class isoenzymes was further confirmed by separation of the mouse liver affinity purified GST by chromatofocusing and also by resolving the GST subunits by reverse-phase high performance liquid chromatographic procedures. Therefore, OPZ induces mainly the mu class isoenzymes in mouse hepatic tissues.

Animals↗
PubMed1993

Agonist-stimulated Cl- efflux from human neutrophils. A common phenomenon during neutrophil activation.

When human peripheral blood neutrophils were stimulated with various agonists which activate and/or prime neutrophils, we found that Cl- efflux was enhanced with a dramatic (50%) loss of intracellular Cl-. Interestingly, the Cl- efflux was enhanced by both agonists which induce a rapid transient increase in intracellular Ca2+ concentration ([Ca2+]i) [class I, e.g. N-formyl-methionyl-leucyl-phenylalanine (fMLP), interleukin-8 (IL8), platelet-activating factor, leukotriene B4 and C5a] and those which do not induce such an [Ca2+]i elevation [class II, e.g. tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. The time course of agonist-stimulated Cl- efflux differed depending on the agonist. Class I agonists such as IL8 and fMLP exhibited a 1 min lag phase before the onset of Cl- efflux; class II agonists such as GM-CSF and TNF displayed a 2 and 5 min lag phase, respectively. Both IL8 (class I)- and TNF (class II)-stimulated Cl- efflux exhibited similar sensitivity to inhibition by different types of ion transport inhibitors [ethacrynic acid (EA), amiloride, 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid, anthracene-9-carboxylic acid, and 4-4'-diisothiocyanatostilbene-2,2'-disulfonic acid]. On the other hand, natural Cl- efflux, which is thought to be mainly mediated by Cl-/Cl- self exchange, was not inhibited by EA (0.5 mM) or amiloride (0.3 mM). These results imply that both class I and class II agonist-stimulated Cl- efflux occurs via a common Cl- transporter which is different from that reported previously in resting human neutrophils. Although all agonists which induced a Cl- efflux also induced shape change of neutrophils, there did not appear to be a causal relationship between shape change and agonist-stimulated Cl- efflux. However, a temporal correlation was found to exist between agonist-stimulated Cl- efflux and intracellular alkalinization following agonist stimulation. Agonist-stimulated Cl- efflux therefore seems to be a common phenomenon activated by several agonists which act through different signal transduction pathways.

Biological Transport↗
PubMed1995

Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver.

In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol. At least one and in some cases all of the three dihydrodiol dehydrogenases reduced each of the ten drugs. Among these naloxone, naltrexone, befunolol, ethacrynic acid and ketoprofen were substrates specific for the dehydrogenases. The other drugs--haloperidol, metyrapone, loxoprofen, daunorubicin and acetohexamide--were highly reduced by carbonyl reductase and/or aldehyde reductase. The dihydrodiol dehydrogenases also showed lower Km values for haloperidol and loxoprofen than did carbonyl reductase. The results indicate that the three dihydrodiol dehydrogenases, as well as the two reductases, are implicated in the reduction of ketone-containing drugs in human liver cytosol.

Alcohol Oxidoreductases↗
PubMed1995

Metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in human placental microsomes.

The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) can be activated metabolically by cytochrome(s) P450 to DNA-damaging agents that result in the formation of tumors in various organs of several animal models. In the present study, 30-min incubations at 37 degrees containing 5 mg/mL pooled human placental microsomes, 36 nmol NNK (including 2 microCi [5-3H]NNK) and a 5 mM concentration of either NADH, NADPH, or both cofactors together resulted in the formation of 11.43 +/- 0.32, 35.40 +/- 4.64, and 44.05 +/- 1.66 pmol 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)/mg protein/min (mean +/- SD, N = 3), respectively. Similar experiments using 7, 9, and 11 mM NADH, NADPH, and both cofactors together in equimolar concentrations yielded results that suggest that NADH- and NADPH-dependent reductions of NNK are catalyzed by different enzymes. Computer simulations for the production of NNAL based on various kinetic models corroborated the conclusion drawn from the empirically derived data. In human placental microsomes, the Km,app and Vmax,app for the formation of NNAL were 1021.9 +/- 251.5 microM and 4360.7 +/- 991.7 pmol/mg protein/min, respectively. Inhibition of cytochrome P450-dependent activities by carbon monoxide and dicumarol (100 and 200 microM) resulted in an average increase of NNAL production of 40 and 56%, respectively, suggesting that P450-dependent biotransformation of NNK is occurring in the absence of inhibitors. Similarly, polyclonal goat IgG against rabbit P450 reductase resulted in a 12% increase in the production of NNAL when compared with control values. Thirty micromolar rutin, ethacrynic acid, cibacron blue 3GA, and iodoacetic acid, known inhibitors of certain human carbonyl reductase(s), incubated with placental microsomes containing an equimolar concentration of NNK, did not have a significant effect on the production of NNAL. These results establish that: (1) cytochromes P450 are likely involved in the metabolism of NNK by human placental microsomes, (2) metabolism of NNK to NNAL by human placental microsomes is catalyzed by an NADPH-dependent carbonyl reductase(s) and an NADH-dependent carbonyl reductase(s), and (3) reduction of NNK to NNAL is catalyzed by a placental microsomal carbonyl reductase(s) not previously described.

Alcohol Oxidoreductases↗
PubMed1981

Methylxanthines modulate adenosine release from slices of cerebral cortex.

Using slices of mouse or rat cerebral cortex incubated with [3H]adenosine or [3H]adenine and/or [14C]GABA we have examined factors affecting the release of these compounds, and especially the influence of methylxanthines. Although release of purines and GABA could be induced by ouabain (10(-4) M), or p-hydroxymercuribenzoate (5 x 10(-4) M) no release was produced by ethacrynic acid (10(-3) or 10(-4) M) phenytoin (10(-3) M), noradrenaline or SC 13504. Release is probably not therefore related to (Na+, K+) ATPase or Mg2+-ATPase inhibition. At concentrations of 10(-3) and 10(-4) M, caffeine, theophylline, aminophylline and isobutyl-methylxanthine (IBMX) markedly depressed the release of purines evoked by ouabain. Non-xanthine inhibition of phosphodiesterase had much weaker though statistically significant effects. The methylxanthines had no significant effect on GABA release. It is suggested that the results can be explained on the basis of a positive feedback system in which released adenosine activates membranal adenylate cyclase, and the increased concentration of cyclic AMP which results form or origin of much of the adenosine released subsequently. However, we cannot exclude the existence of an intracellular receptor for methylxanthines which causes directly the inhibition of purine release.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Are Ca2+-dependent proteases really responsible for Cl(-)-dependent and Ca2+-stimulated binding of [3H]glutamate in rat brain?

The role of Ca2+ ions in [3H]glutamate binding was re-examined using synaptic membranous preparations obtained from the rat brain. In vitro addition (0.1-5 mM) of calcium chloride exhibited a profound enhancement of the binding in a temperature-dependent manner, whereas that of calcium acetate had no significant effect on the binding independently of the incubation temperature. Calcium acetate elicited a significantly additional stimulation of the Cl(-)-induced and temperature-dependent facilitation of the binding. The augmentation by these two ions was invariably eliminated by the addition of an antagonist for the anion channels including picrotoxinin as well as of inhibitors of anion transport such as ethacrynic acid and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid. L-Aspartate exerted a more potent inhibitory action on the Cl(-)-dependent binding and Cl(-)-dependent and Ca2+-stimulated binding, than D-aspartate. The latter two bindings were selectively abolished by an agonist (quisqualic acid) and an antagonist (DL-2-amino-4-phosphonobutyric acid) for central glutamate receptors, respectively. It was also found that pretreatment of the membranes with calcium acetate resulted in a complete abolishment of the Ca2+-stimulated binding with a concomitant stimulation of the Cl(-)-dependent binding, which invariably occurred independently of the preincubation temperature (2 or 30 degrees C). No significant alteration was detected in the basal binding following the latter pretreatment. None of various protease inhibitors such as leupeptin, antipain, chymostatin and pepstatin induced a significant alteration in the basal, Cl(-)-dependent, Ca2+-stimulated and Na+-dependent bindings of [3H]glutamate, respectively. These results suggest that Ca2+ ions may elicit their stimulatory action on the Cl(-)-dependent binding of [3H]glutamate even in the absence of Cl- ions added through the temperature-independent and apparently irreversible interaction with the anion transport carriers rather than the direct action on the binding sites of the ligand. The evidence presented here also suggests that the widely held view that Ca2+-dependent proteases are responsible for the exhibition of Cl(-)-dependent and Ca2+-stimulated binding of [3H]glutamate may need to be re-evaluated.

Animals↗
PubMed1992

Schistosoma mansoni: single-step purification and characterization of glutathione S-transferase isoenzyme 4.

A soluble glutathione S-transferase isoenzyme, designated SmGST-4 was purified to apparent homogeneity in a single step from the cytosol of adult Schistosoma mansoni by selective elution of the enzyme from a glutathione-agarose affinity column using glutathione disulfide. SmGST-4, which comprised about 5% of the bound glutathione S-transferase activity, could be distinguished from the previously characterized glutathione S-transferase isoenzyme family (SmGST-1/2/3), by its unique chromatographic behavior, lower subunit M(r) (26,000), differences in substrate specificity and inhibitor sensitivity, and a lack of reactivity with antiserum to SmGST-3. The purified isoenzyme catalyzed the conjugation of several model xenobiotics including 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and trans-4-phenyl-3-buten-2-one. Like the SmGST-1/2/3 isoenzyme family, SmGST-4 failed to catalyze the conjugation of a model epoxide substrate, 1,2-epoxy-3-(p-nitrophenoxy)propane. Because glutathione S-transferases from other organisms play a role in protecting cells against the toxic products of lipid peroxidation, SmGST-4 and the members of the SmGST-1/2/3 isoenzyme family were tested for their capacity to reduce cumene hydroperoxide and to catalyze the conjugation of 4-hydroxyalk-2-enals. Although all four isoenzymes catalyzed both reactions, the specific activity of SmGST-1, SmGST-2, and SmGST-3 toward cumene hydroperoxide was at least 10-fold greater than that of SmGST-4. In contrast, the latter more effectively conjugated a homologous series of 4-hydroxyalk-2-enal isomers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Rat glutathione transferase 8-8, an enzyme efficiently detoxifying 4-hydroxyalk-2-enals.

Rat glutathione transferase 8-8 is one of the less abundant cytosolic glutathione transferases, accounting for approx. 1% of the total activity with 1-chloro-2,4-dinitrobenzene in liver. The enzyme is eluted at pH 6.3 upon chromatofocusing and has so far been identified in liver, kidney, lung and testis. Characteristic properties include high relative activity with ethacrynic acid (70% of the specific activity with 1-chloro-2,4-dinitrobenzene) and an apparent subunit Mr of 24 500. The most significant property noted is the high catalytic activity in the conjugation of 4-hydroxyalk-2-enals, major products of lipid peroxidation. The catalytic efficiency with these substrates exceeds corresponding values for all known substrates tested with any glutathione transferase, which suggests that transferase 8-8 may have evolved to detoxify 4-hydroxyalk-2-enals.

Animals↗
PubMed1988

Characterization of the activation of rat liver glutathione S-transferases by nonsubstrate ligands.

In previous work (D.A. Vessey and T.D. Boyer, 1986, Biochem. Pharmacol., 35, 289-295) the activity of glutathione S-transferase form YcYc from rat liver was found to be stimulated by the herbicide 2,4,5-T. We have extended that work and examined the effect of over 40 structural analogs on the activity of YcYc. Over half of these compounds stimulated by 10 to 232% when added to assays at a concentration of 1 mM. The best activators all contained the "2,4,5-trichlorophenyl-" structure. While 2,4,5-T gave the greatest activation at 1 mM (2.3-fold), 2,4,5-trichlorobenzene sulfonate gave the greatest maximum activation (6.0-fold). Compounds that had no effect on activity did not affect activation by 2,4,5-T suggesting that they have a poor affinity for the enzyme. Two of the analogs tested (chloramine-T and 6-hydroxydopamine) proved to be good inhibitors and ethacrynic acid was an extremely potent inhibitor. Indomethacin activated at low concentrations but inhibited above 2 mM. Activations were greater at low temperature (5 degrees C) and decreased with increasing temperature. The extent of activation was largely unaffected by the concentration of either substrate. Examination of the organic peroxidase activity of the enzyme revealed inhibition by 2,4,5-T and 2,4-D rather than activation.

2,4,5-Trichlorophenoxyacetic Acid↗
PubMed1988

The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats.

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.

Animals↗
PubMed1994

A possible role for extracellular bicarbonate in U-46619-induced rat platelet aggregation.

U-46619, a thromboxane A2 agonist, has been believed not to induce aggregation of rat platelets. However, we have found that U-46619 evoked rat platelet aggregation when the cells were suspended in HCO3-containing medium, whereas it was inactive in medium lacking HCO3-. 4,4'-Diisothiocyanostilbene-2,2'-disulfonate (DIDS), selective inhibitor of the HCO3/Cl- exchanger, inhibited the aggregation of rat platelets induced by U-46619 as well as by collagen and ADP. Thrombin-induced aggregation was also inhibited by DIDS, although to a much lesser extent. Several inhibitors of anion transporters, such as phloretin, pyridoxal phosphate and ethacrynic acid, suppressed U-46619-induced aggregation. These observations indicate that HCO3-influx via an anion exchanger may be involved in the signal transduction pathway of U-46619 in rat platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1975

The reaction of PGA1 with sulfhydryl groups; a component in the binding of A-type prostaglandins to proteins.

Prostaglandins of the A-type (PGAs) were found to react with cysteine or reduced glutathione to yield water-soluble adducts, an effect due to a reaction of the sulfhydryl group of cysteine with the unsaturated carbonyl function of these prostaglandins. The binding of tritiated PGA1 to the supernatant fraction of rabbit papilla homogenates reported by Attallah and Lee (4) appears to be related to this phenomenon since ethacrynic acid, a compound also highly reactive with the thiol group of cysteine, effectively competes with PGAs for the binding site in this soluble kidney preparation. Evidence is also presented to show that this binding of PGAs to the "acceptor' of the rabbit kidney is related to an interaction with a thiol group of 15-hydroxy prostaglandin dehydrogenase, the enzyme chiefly involved in the metabolism of prostaglandins.

Animals↗