Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently reported that co-administration to female mice of tamoxifen or 4-hydroxytamoxifen (4-OH-tamoxifen) with pentachlorophenol (PCP), but not with 2,6-dichloro-4-nitrophenol (DNCP) results in strong intensification of a specific subgroup, termed group I, of tamoxifen-DNA adducts in female mouse liver. As both PCP and DCNP are sulfotransferase inhibitors, we concluded that the intensification of tamoxifen group I adducts is probably not due to inhibition of sulfation by these phenols of a tamoxifen metabolite. Since epoxide derivatives of 4-OH-tamoxifen are potential candidates involved in tamoxifen-induced DNA damage, the hypothesis was developed and tested that PCP inhibits epoxide detoxication. As 4-OH-tamoxifen metabolites were unavailable to us, we employed indirect approaches to test this hypothesis. In the first set of experiments we determined whether PCP would augment DNA adduct formation from the benzo[a]pyrene metabolite, 9-hydroxybenzo[a]pyrene (9-OH-BP), as 9-OH-BP-4,5-epoxide is known to be involved in the metabolic activation of this compound. Female mice were given a single i.p. dose of 9-OH-BP (50 mumol/kg) either alone or in combination with PCP (75 mumol/kg), and hepatic DNA adducts were measured 24 h later by nuclease P1-enhanced bisphosphate 32P-postlabeling. Co-administration of PCP with 9-OH-BP resulted in a statistically significant 1.5- to 1.7-fold increase in 9-OH-BP adduct levels versus 9-OH-BP controls. In order to determine whether PCP inhibits the enzymatic detoxication of epoxides in vitro, in a second set of experiments, the effects of PCP on liver microsomal epoxide hydrolase (mEH) and purified equine liver glutathione S-transferase (GST) activities were studied using, respectively, styrene-7,8-oxide and 1-chloro-2,4-dinitrobenzene (CDNB) as substrates. Incubation of mouse liver microsomes with PCP (10-100 microM) strongly inhibited (by 21-97%) mEH activity in a dose-dependent manner, the IC50 being 35 microM. DCNP was ineffective as a mEH inactivator. PCP also inhibited purified equine liver GST activity, with an IC50 of 23.5 microM. Taken together, the results of this study strongly support the hypothesis that PCP inhibited enzymatic detoxication of epoxides in vivo and in vitro. By this mechanism PCP would lead to enhancement of DNA damage caused by 9-OH-BP, and possibly other drugs and their metabolites, which undergo epoxidation prior to DNA binding.
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PMID:Pentachlorophenol enhances 9-hydroxybenzo [a] pyrene-induced hepatic DNA adduct formation in vivo and inhibits microsomal epoxide hydrolase and glutathione S-transferase activities in vitro: likely inhibition of epoxide detoxication by pentachlorophenol. 889 15

The effects of thiazole (TH), benzothiazole (BT) and benzothiadiazole (BZ) on the expression of hepatic glutathione S-transferases (GSTs) Ya, Yb1, Yb2, Yc1 and Yc2 and microsomal epoxide hydrolase (mEH) genes were compared in rats. TH treatment resulted in 4- to 24-fold increases in GST Ya mRNA levels at 24 hr posttreatment; the ED50 value was 70 mg/kg. GST Ya mRNA levels were elevated 13-, 20-, 20- and 9-fold at 12, 24, 48 and 72 hr following 100 mg/kg of TH treatment, respectively, as compared with the control. BT was a moderate inducer of GST Ya with a maximal 18-fold increase observed, whereas BZ treatment caused a transient increase in GST Ya mRNA at 12 hr posttreatment, followed by a return to a 4-fold relative increase at 24 hr or afterward. Treatment of rats with TH at the dose of 100 mg/kg resulted in an approximately 10-fold increase in either Yb1 or Yb2 mRNA levels at 24 hr posttreatment. BT-treated rats showed 7- and 3-fold increases in the GST subunit Yb1 and Yb2 mRNA levels at 24 hr posttreatment. BZ was the least effective in modulating either GST Yb1 or Yb2 mRNA, resulting in < 2-fold changes. GST Yc1 and Yc2 mRNA levels were increased approximately 8-fold at the dose of 200 mg/kg of TH. BT minimally affected GST subunit Yc1 and Yc2 mRNA levels, with a maximal 4-fold relative increase observed. BZ was the least effective in enhancing Yc1 and Yc2 mRNA levels. Protein levels for GST subunit Ya, Yb1, Yb2 and Yc were also elevated in response to TH by 3-, 2-, 2-, and 2-fold, respectively. Thus, TH was effective in modulating both constitutive and inducible GST gene expression. BT or BZ was much less effective in increasing the expression of GST subunits. These RNA and Western blot analyses revealed that the levels of major GST were differentially increased after treatment with these thiazoles, exhibiting a rank order of GST expression of TH > BT > BZ. mEH expression by these compounds appeared to be consistent with that of GST Ya. The mRNA levels for GST Ya, Yb1, Yb2, Yc1 and Yc2 and mEH were also determined after treatment with triazole (TR), imidazole (IM), benzoxazole (BX), benzotriazole (BTR) or benzimidazole (BIM). TR, IM, BX or BTR caused increases in Ya, Yb1, Yc1 and Yc2 mRNA levels by 2- to 3-fold, whereas the agents failed to modulate the expression of GST Yb2. The fact that benzene, cyclohexane or n-hexane minimally affected the major GST or mEH mRNA levels provided evidence that certain heterocyclic compounds are more capable of modulating GST or mEH gene expression than hydrocarbons. These results corroborate evidence that the thiazoles differentially stimulate GST or mEH genes, with TH being the most efficacious; that thiazoles with carbocyclic ring are much less effective in increasing GST or mEH levels than is TH; and that the changes in these GST and mEH levels are primarily associated with increases in mRNA levels.
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PMID:Expression of glutathione S-transferases Ya, Yb1, Yb2, Yc1 and Yc2 and microsomal epoxide hydrolase genes by thiazole, benzothiazole and benzothiadiazole. 895 41

Rats treated with quinoline, and to a lesser extent, isoquinoline (75 mg/kg, daily for 3 days) showed induction of phase II drug metabolizing enzyme activities without inducing either cytochrome P450 concentration or CYP1A-, CYP2B-, CYP2E-, and CYP3A-selective activities. Elevations of UDP-glucuronosyltransferase activities towards 4-nitrophenol, 1-naphthol, and morphine elicited by quinoline (1.9- to 2.7-fold), were greater than those elicited by isoquinoline (1.4- to 1.8-fold). UDP-glucuronosyltransferase activities towards estrone and testosterone were not increased by either compound. Microsomal epoxide hydrolase activity was increased only by quinoline (2.7-fold). NAD(P)H quinone oxidoreductase activity was increased 2-fold by quinoline and isoquinoline. Cytosolic glutathione S-transferase (GST) activity was increased similarly (approximately 20%) by both agents. Similar treatment of rats with either quinine (75 mg/kg) or chloroquine (150 mg/kg) increased 1-naphthol glucuronidation and GST (quinine only) activities. At 75 mg/kg, chloroquine did not affect any phase II enzyme activities but caused a minor elevation of a phase I enzyme, CYP1A; ascertained from an elevation of 7-ethoxyresorufin deethylase activity and a small hypsochromic shift to the absorbance maximum of the cytochrome P450 CO-complex. With quinoline and isoquinoline treatments (n = 14), the correlation coefficients (R) between microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine were 0.96 and 0.92 respectively, suggesting a highly coordinated induction. The highest NAD(P)H quinone oxidoreductase correlations were with microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine (R approximately 0.78). Correlation coefficients between GST and microsomal epoxide hydrolase and NAD(P)H quinone oxidoreductase activities were approximately 0.49. Quinoline and isoquinoline, nitrogen heterocyclic analogs of naphthalene, join the list of simple nitrogen-containing polycyclic aromatic agents capable of selective induction of phase II drug metabolizing enzymes. The position of the single heterocyclic nitrogen atom in the bicyclic ring influences the magnitude and breadth of the induction response. The addition of bulky ring substituents (quinine, chloroquine) reduced the induction response.
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PMID:Selective induction of phase II drug metabolizing enzyme activities by quinolines and isoquinolines. 913 7

Rats were treated with nitrogen-containing phenanthrene (3,4-, 5,6-, or 7,8-benzoquinoline) or anthracene (acridine or quinacrine) derivatives at a dose of 75 mg/kg, daily for 3 days. The hepatic drug metabolizing enzyme response ranged from no induction (quinacrine) through low (5,6-benzoquinoline), intermediate (acridine), and high (3,4-benzoquinoline) magnitude increases of only phase II enzymes, to induction of both phase I and phase II enzymes (7,8-benzoquinoline). The phase I enzyme response of 7,8-benzoquinoline was an induction of CYP1A. All three benzoquinolines, but neither anthracene derivative, elevated NAD(P)H quinone oxidoreductase activity. A similar pattern but of lesser magnitude was seen with glutathione S-transferase activity. 3,4-Benzoquinoline was the only agent to significantly increase microsomal epoxide hydrolase activity (2,3-fold). Both 3,4- and 7,8-benzoquinoline increased UDP-glucuronosyltransferase activity toward 4-nitrophenol (40% and 70%, respectively), but only the 3,4-isomer increased activity toward morphine (75%), diclofenac (75%), and testosterone (23%), and only the 7,8-isomer increased activity toward chloramphenicol (105%). 3,4-Benzoquinoline elevated the hepatic mRNA concentration of UGT2B1 but not UGT1*6. Acridine treatment increased UDP-glucuronosyltransferase activity toward morphine (47%), 1-naphthol (28%), testosterone (19%), and estrone (19%). Quinacrine failed to elevate any UDP-glucuronosyltransferase activity and depressed activities toward testosterone and estrone by 20%. This study shows that some tricyclic aromatic compounds containing a single heterocyclic nitrogen atom have the potential for use as chemoprotective agents based upon their ability to selectively induce only phase II enzymes.
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PMID:Drug metabolizing enzyme induction by benzoquinolines, acridine, and quinacrine; tricyclic aromatic molecules containing a single heterocyclic nitrogen. 917 41

The effects of gadolinium chloride, a Kupffer cell toxicant, on the constitutive and inducible expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) genes were examined in rats. Northern blot analysis showed that treatment of rats with GdCl3 caused suppression of mEH and GST gene expression. mEH mRNA levels were decreased in a time-dependent manner after a single injected dose of GdCl3 (10 mg/kg, iv), resulting in 95, 55, 17, 36, and 69% of the levels in untreated animals at 6, 12, 18, 24, and 48 hr after treatment, respectively. A maximal reduction in GST Ya, Yb1/2, and Yc1 mRNA levels was also noted at 18 hr after treatment with GdCl3, followed by a gradual return to levels in untreated rats at later time points. Whereas treatment of rats with thiazole, allyl disulfide, propyl sulfide, oltipraz, or clotrimazole caused 2-13-fold increases in mEH mRNA levels at 18 hr after treatment, concomitant GdCl3 treatment caused 30-70% reductions in the increases in mEH mRNA levels. The chemical-inducible mRNA levels for GST Ya, Yb1/2, and Yc1 were also significantly inhibited by GdCl3 at 18 hr after treatment. Rats treated with GdCl3 (10 mg/kg/day, iv) for 3-5 consecutive days exhibited 40-90% decreases in mEH, GST Ya, and GST Yb1/2 mRNA levels, relative to control, whereas the Yc1 mRNA level was suppressed at early times and returned to levels in untreated animals at day 5 after treatment. The mRNA levels for mEH and GST Ya in rats treated daily with both allyl disulfide (25 mg/kg, po) and GdCl3 for 3 consecutive days were 20-30% of those in rats treated with allyl disulfide alone. Western immunoblotting showed that mEH and GST Ya protein expression was decreased at 1-3 days after consecutive daily treatment with GdCl3. Whereas treatment of rats with GdCl3 at a dose of 1 mg/kg suppressed constitutive hepatic mEH gene expression by 85% at 18 hr, rats treated with CaCl2 (10 mg/kg, iv) in combination with GdCl3 (1 mg/kg, iv) showed 45% suppression of the mEH mRNA level, compared with untreated animals. GdCl3-induced suppression was also significantly reversed for GST Ya mRNA by excessive CaCl2 administration. These results demonstrate that GdCl3 effectively inhibits constitutive and inducible mEH and GST expression, with decreases in their mRNA levels. GdCl3 suppression of detoxifying enzyme expression may be associated with its blocking of intracellular Ca2+ influx, which affects signaling pathways for the expression of the genes.
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PMID:Gadolinium chloride inhibition of rat hepatic microsomal epoxide hydrolase and glutathione S-transferase gene expression. 939 32

The effects of acriflavine (ACF), a protein kinase C inhibitor, on the expression of hepatic microsomal epoxide hydrolase (mEH), glutathione S-transferases (GSTs), and cytochrome P450 (P450) were assessed in rat hepatic tissue. Northern blot analysis revealed that treatment of rats with thiazole, allyl disulfide (ADS), oltipraz, or clotrimazole at a single dose of 100 mg/kg resulted in 7-18-fold increases in mEH mRNA levels at 24 hr, whereas concomitant ACF treatment (20 mg/kg, im) caused 50-95% inhibition of the chemical-induced increases in hepatic mEH mRNA levels. rGSTA2, rGSTA3, and rGSTM1 mRNA levels were also significantly suppressed at 24 hr in response to a single dose of ACF (20 mg/kg, im). Animals treated with both ACF and ADS showed complete blockage of mEH and GST gene expression as early as 12 hr after treatment. ADS-inducible increases in mEH and rGSTA2 mRNA levels were suppressed at 24 hr after treatment with ACF, in a dose-related manner, with 50% inhibitory dose (ID50) values of 2.0-2.3 mg/kg, whereas glyceraldehyde-3-phosphate dehydrogenase mRNA levels were not altered. Immunoblot analysis revealed that ACF (15 mg/kg/day, im, for 3 days) inhibited induction of mEH or rGSTA2 protein by ADS (100 mg/kg/day, po, for 3 days). The levels of hepatic P450 2B1/2, P450 2C11, and P450 3A1/2 were decreased in rats treated with ACF (15 mg/kg/day, im, for 3 days), whereas P450 1A2 and P450 2E1 expression was not affected. Treatment of rats with ACF in combination with gadolinium chloride, which inhibits mEH and GST expression through calcium channel blocking, shifted the dose-inhibitory response curves for ACF to the left, with 7-15-fold decreases in the ID50 values, indicating that the active site for ACF for suppression of mEH and GST mRNA levels differs from that for gadolinium chloride. Proflavine and safranine O, which are structurally related to ACF, also caused suppression of ADS-induced increases in mRNA levels, in a dose-dependent manner, with ID50 values of 4-9 mg/kg. These results demonstrate that ACF and its related compounds effectively suppress the expression of a battery of hepatic xenobiotic-metabolizing enzymes, including mEH, GSTs, and certain P450 forms.
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PMID:Suppression of xenobiotic-metabolizing enzyme expression in rats by acriflavine, a protein kinase C inhibitor. Effects on epoxide hydrolase, glutathione S-transferases, and cytochromes p450. 944 55

1. 2-(Allylthio)pyrazine protects the liver against acetaminophen- and carbon tetrachloride-induced injury through inhibition of cytochrome P4502E1 and induction of glutathione S-transferases (GSTs). By comparison, the effects of allylthiobenzimidazole (ATB) on the levels of several hepatic cytochrome P450, microsomal epoxide hydrolase (mEH) and GST expression have been studied in the rat herein. 2. Western immunoblotting analyses revealed that ATB treatment (50 mg/kg/day for 5 days) failed to alter cytochrome P4501A2, P4502B1/2 and P4502E1 levels in the liver, whereas the expression of P4502C11 was reduced approximately 50% by ATB. 3. Treatment of rat with a single dose of ATB resulted in 2-21-fold increases in mEH mRNA levels at 24 h with an ED50 = 60 mg/kg. mEH mRNA level was elevated 9- and 21-fold at 12 and 24 h after treatment at 200 mg/kg respectively as compared with control. Western blot analysis revealed that ATB induced mEH protein levels by 2-fold relative to control. 4. ATB induced the major GST mRNA levels as a function of dose, resulting in rGSTA2, rGSTA3/5 and rGSTM1 mRNA levels elevated by 20-, 6- and 8-fold at 24 h respectively. The relative rGSTM2 mRNA level was minimally affected. Time-course studies showed that mEH, rGSTA2 and rGSTM1 mRNA levels were significantly increased at 12 and 24 h after ATB treatment, returning to control levels by 48 h. Treatment of rat with ATB (20-50 mg/kg/day for 5 days) resulted in 2-3-fold increases in mEH, rGSTA1/2, rGSTA3/5 and rGSTM1 mRNA levels with the induction of GST subunits. 5. ATB failed to block carbon tetrachloride-induced liver toxicity in rat and mouse. ATB treatment (50 mg/kg day for 3 days) prior to a lethal dose of acetaminophen significantly reduced acetaminophen-induced liver toxicity in mouse, as assessed by both plasma alanine aminotransferase activity and histopathological examination. The 30-day survival rate of mouse gamma-irradiated at 8 Gy failed to be improved by ATB pretreatment (100 mg/kg/day for 2 days). 6. These results provided evidence that ATB stimulated mEH and GST gene expression at early times and reduced the P4502C11 level in the absence of P4502E1 suppression. ATB was only partially effective in protecting the liver against toxicant-induced injury despite the presence of allylthio moiety in its chemical structure.
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PMID:Partial hepatoprotective effects of allylthiobenzimidazole in the absence of cytochrome P4502E1 suppression: effects on epoxide hydrolase, rGSTA2, rGSTA3/5, rGSTM1 and rGSTM2 expression. 957 20

Previous studies in this laboratory have shown that oltipraz (Olt), a chemopreventive agent, enhances radiation(Rad)-inducible glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) expression in the liver. The present study was designed to investigate the in vivo radioprotective effect of Olt in ICR mice exposed to a lethal dose of Rad. The 30-day survival rate of mice irradiated at the dose of 8 Gy was substantially increased to 91% by Olt pretreatment (100 mg/kg/day for 2 days), compared with 48% in animals irradiated alone. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray Rad resulted in hepatocyte degeneration in the surviving animals from Day 1 through Day 22 after irradiation with certain degrees of necrosis observed at early times, whereas Olt treatment provided protection of the liver against irradiation with no hepatic necrosis noted. Mice irradiated at the dose of 8 Gy exhibited time-related decreases in the white blood cell (WBC), red blood cell (RBC), and platelet counts with maximal reduction noted at Day 10. Animals irradiated with Olt treatment showed no difference in peripheral blood cell counts or in the ratio of myeloid to erythroid bone marrow cells, compared with those irradiated alone. Northern RNA blot analysis showed that treatment of mice with Olt at the dose of 100 mg/kg in combination with 8 Gy irradiation resulted in 12-fold increases in hepatic mEH and mGSTA3 mRNA levels at 24-hr post-treatment, whereas mGSTP1 mRNA levels were not altered. The mRNA levels for mEH and mGSTA3 were elevated after exposure of animals to both Olt and 8 Gy-gamma ray to a greater extent than after irradiation alone. The enhanced survival rate (91%) in 8 Gy-irradiated animals after treatment with Olt (100 mg/kg/day for 2 days) was completely reversed by concomitant pretreatment with dexamethasone (Dexa) (0.1 and 1 mg/kg/day for 2 days), a known inhibitor of mEH and GST expression, resulting in a 42% and 28% survival rate, respectively. Mice irradiated after dexamethasone treatment at a dose of 1 mg/kg showed a reduced mean survival time compared with those treated with 0.1 mg/kg of dexamethasone (9 vs 14 days). The current study demonstrates that Olt is effective in increasing the survival rate of mice against ionizing Rad and that protective effects of Olt associated with enhanced expression of mEH and GST genes may represent its radioprotective efficacy.
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PMID:In vivo radioprotective effects of oltipraz in gamma-irradiated mice. 963 94

Previous studies in this laboratory have shown that gamma-ray ionizing radiation in combination with oltipraz, a radioprotective agent, enhances hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) expression. The present study was designed to investigate the effects of dexamethasone on the radiation-inducible expression of mEH and rGST genes and on the vitamin C and E-induced radioprotective effects in association with the expression of the genes. Treatment of rats with a single dose of dexamethasone (0.01-1 mg/kg, p.o.) caused a dose-dependent decrease in the constitutive mEH gene expression at 24 hr. The radiation-inducible mEH mRNA level (threefold increase after 3 Gy gamma-irradiation) was decreased by 21% and 88% by dexamethasone at the doses of 0.1 and 1 mg/kg, respectively. Although dexamethasone alone caused 2- to 5-fold increases in the hepatic rGSTA2 mRNA level, rats treated with dexamethasone prior to 3 Gy irradiation exhibited 80%-93% suppression in the radiation-inducible increases in the rGSTA2 mRNA level. The inducible rGSTA3 and rGSTA5 mRNA levels were also significantly decreased by dexamethasone, whereas the rGSTM1 mRNA level was reduced to a lesser extent. Vitamin C and/or E, however, failed to enhance the radiation-inducible increases in hepatic mEH and rGST mRNA levels. Whereas rats exposed to 3 Gy irradiation with or without vitamin C treatment (30 or 200 mg/kg/day, p.o., 2 days) exhibited approximately threefold increases in the mEH and rGSTA2/3/5 mRNA levels relative to untreated animals, dexamethasone treatment (1 mg/kg, p.o.) resulted in 64%-96% decreases in the mRNA levels at 24 hr. The inducible rGSTM1/2 mRNA levels in the vitamin C/E-treated rats were approximately 50% suppressed by dexamethasone. Although vitamin C and/or E treatment (200 mg/kg/day, p.o., 2 days) improved the 30-day survival rates of the 8 Gy gamma-irradiated mice from 39% up to 74%, the improved survival rate of gamma-irradiated animals was reduced to 30% by dexamethasone pretreatment (1 mg/kg/day, 2 days). The mean survival time of dexamethasone-treated animals was reduced to approximately 2 days from 14 days in the animals with total body irradiation alone. No significant hematologic changes were observed in mice at 10 days after dexamethasone plus gamma-irradiation, as compared with irradiation alone. These results demonstrate that: dexamethasone substantially suppresses radiation-inducible mEH, rGSTA and rGSTM expression in the liver; vitamins C/E exhibit radioprotective effects without enhancing radiation-inducible mEH and GST gene expression; and inhibition of radiation-inducible mEH and rGST gene expression in the vitamin C- and E-treated animals by dexamethasone was highly correlated with reduction in the survival rate and the mean survival time of gamma-irradiated animals.
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PMID:Correlation of increased mortality with the suppression of radiation-inducible microsomal epoxide hydrolase and glutathione S-transferase gene expression by dexamethasone: effects on vitamin C and E-induced radioprotection. 982 28

Lipopolysaccharide (LPS) is an endotoxin involved in septic shock syndrome and potentiates toxicant-induced liver injury. The effects of LPS on the constitutive and inducible expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) genes were studied in rats. Northern blot analysis showed that treatment of rats with LPS caused suppression in mEH and GST gene expression. The mEH mRNA level was decreased in a time-dependent manner following a single dose of LPS (1 mg/kg, i.v.), resulting in levels of 52%, 22%, 17%, and 94% of those in untreated animals at 2, 6, 12, and 24 hr, respectively. The levels of rGSTA2 and rGSTA3 mRNA were suppressed in response to an LPS injection to the similar extents as observed in mEH mRNA, whereas rGSTM1 and rGSTM2 mRNA levels were less affected. LPS inhibited mEH gene expression at the doses of 1 microg or greater. Whereas treatment of rats with allyl disulfide (ADS), oltipraz (OZ) or pyrazine (PZ) at the dose of 50 mg/kg caused increases in the mEH mRNA level at 12 hr, a concomitant LPS injection (1 mg/kg) resulted in 80%-95% suppression of the inducible gene expression. The inducible rGSTA2, rGSTA3, rGSTM1, and rGSTM2 mRNA levels were also 50%-90% decreased at 12 hr after LPS treatment, with the relative change in rGSTA being greater than that in rGSTM. Three consecutive daily treatments with LPS (10 microg/kg/day) resulted in significant decreases of the constitutive and PZ (50 mg/kg/day, i.p. for 3 days)-inducible mEH and GST mRNA levels, which were consistent with those in the protein levels. Gel shift retardation analysis showed that LPS substantially activated the hepatic nuclear p65/p50 nuclear factor-kappaB (NF-kappaB) complex with the maximal effect observed at 1 hr at the doses of 1 microg/kg or greater. LPS-induced activation of nuclear NF-kappaB (1 microg/kg, i.v.) failed to be inhibited by concomitant treatment with the mEH and GST inducers, including ADS (300 mg/kg, p.o.), OZ (300 mg/kg, p.o.), and PZ (300 mg/kg, i.p.), indicating that NF-kappaB activation was not required for suppression of the gene expression by LPS. In contrast, GdCl3, an inhibitor of mEH and GST expression, inhibited LPS-induced activation of the p65/p50 NF-kappaB. These gel shift analyses provided evidence that LPS-induced activation of the NF-kappaB was not responsible for alterations in the gene expression. In summary, the results of this research demonstrate that LPS effectively inhibits constitutive and inducible mEH and GST expression with decreases in their mRNA levels, and that LPS suppression in the expression of the detoxifying enzymes is not mediated with its activation of NF-kappaB.
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PMID:Lipopolysaccharide inhibition of rat hepatic microsomal epoxide hydrolase and glutathione S-transferase gene expression irrespective of nuclear factor-kappaB activation. 982 74


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