Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The lung is a target organ for the toxic effects of several chemical agents, including natural products, industrial chemicals, pesticides, environmental agents, and occasionally, drugs. Factors that establish the lung as a target organ include selective tissue exposure, high tissue oxygenation, and the presence of bioactivating systems that can generate toxic products from initially innocuous substances. Selective pulmonary exposure most often results from the fact that the lung serves as the major portal of entry for most airborne substances, but in some cases, selective exposure is the consequence of accumulation of agents, such as certain basic amines, from the circulation. Lung tumor development following long-term exposure to cigarette smoke or diesel engine exhaust is an example of pulmonary toxicity resulting from selective external exposure. Selective internal exposure, on the other hand, is exemplified by the pulmonary uptake of the herbicide paraquat from the circulation which is in part responsible for its lung-toxic effects. Although the lung contains drug metabolizing enzymes similar to those found in the liver, the enzymatic systems in the lung are sometimes highly concentrated in specific cell types. In the rabbit, for example, the lung-selective toxicity of the natural product ipomeanol is the consequence of relatively large amounts of cytochromes P450 2B1 and 4B1 in nonciliated bronchiolar epithelial cells (Clara cells) of the terminal airways. These P450 enzymes are highly proficient in vitro at converting ipomeanol to reactive products. Lung tissue contains other enzymic systems which are capable of catalyzing phase I biostransformation pathways (e.g., flavin-containing amine monooxygenase, amine oxidase, and prostaglandin synthase). Examples, however, where pulmonary metabolism by these pathways results in lung toxicity are less numerous than with P450 mediated reactions. Pulmonary prostaglandin H-synthase mediated cooxygenation has been shown to activate procarcinogens such as benzo(a)pyrene 7,8-dihydrodiol, aflatoxin B1, and monosubstituted hydrazines. The activities of pulmonary phase II (conjugation) pathways may also contribute to lung toxicity. Low glutathione transferase activity (relative to P450 mediated aryl hydrocarbon hydroxylase activity) in lung tissue has been suggested to correlate with elevated risk of lung cancer in smokers. Other examples of lung-specific toxic agents and possible causative roles of biotransformation are also discussed.
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PMID:The role of metabolism in chemical-induced pulmonary toxicity. 181 90

Polychlorinated biphenyls (PCBs) are a group of industrial chemicals that are widely distributed in the environment. Because these compounds occur as mixtures, studies of their possible interactive effects are essential for an understanding of the mechanism of the toxicity of these mixtures. For the determination of a possible interaction of the effects in vivo of 2,5,2',5'-tetrachlorobiphenyl (TCB) and 3,4,3',4'-TCB, rats were exposed to a single dose of diethylnitrosamine (DEN) and subsequently to 0.1 p.p.m. 3,4,3',4'-TCB and/or 10 p.p.m. 2,5,2',5'-TCB in the feed for 1 year. The two major targets of PCB toxicity, the liver and the peripheral blood, were examined after these treatments. TCB treatment after DEN exposure caused a predominance of increased placental glutathione S-transferase (PGST) and deficiencies of ATPase as preneoplastic markers in focal hepatic lesions. When 0.05% phenobarbital (PB) was administered after DEN exposure, the distribution of markers in altered hepatic foci (AHF) was essentially equal for increased PGST and gamma-glutamyltranspeptidase (GGT) and for ATPase deficiency. Many of these AHF also exhibited increased P450 b/e expression. Our results demonstrated that the two PCB congeners interacted in vivo to produce an increase in AHF that were PGST positive and ATPase negative. PGST-positive and ATPase-negative AHF correlated best with focal areas of P450 b/e expression. The combination of the two PCBs caused a greater than additive decrease in the total number of lymphocytes and antibody-producing B-cells. Also the thymocyte-dependent T-helper cells isolated from the animals receiving the combination of TCBs demonstrated a morphologically abnormal subpopulation. The results indicate that the interaction of 2,5,2',5'-TCB and 3,4,3',4'-TCB in vivo induced much greater toxicity and mutagenicity in peripheral lymphocytes and hepatocytes than treatment with either congener alone.
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PMID:Study of the separate and combined effects of the non-planar 2,5,2',5'- and the planar 3,4,3',4'-tetrachlorobiphenyl in liver and lymphocytes in vivo. 182 16

Aflatoxin B1 (AFB1) appears to be a risk factor for upper respiratory tumors in individuals occupationally exposed to AFB1-contaminated grain dusts. To study the potential effects of this mycotoxin in the upper airways, the metabolism of AFB1 was investigated in tracheal cultures and purified tracheal microsomes from rabbit, hamster and rat. These species differ in the proportion of P450-containing non-ciliated epithelial (NC) cells in the upper airway (17, 41, 0% respectively). Cultures from the rabbit produced the highest level of the AFB1 metabolites AFB1-dihydrodiol (AFB1-diol), GSH-AFB1, AFM1, AFB2a and the highest tracheal microsomal pentoxyresorufin-O-dealkylase (PROD) activity (an indicator of that P450 activity which activates AFB1) and greater cytosolic GSH-transferase activity compared to hamster and rat. Tracheal microsomal epoxide hydrolase activity, AFB1-diol production, cytochrome P450 content, P450 reductase and ethoxyresorufin-O-dealkylase (EROD) activity (an indicator of AFB1 detoxification) were highest in the hamster. Although the overall metabolic activity in rat tracheal epithelium was low, PROD-related activity appeared to predominate. Conjugation with GSH was the major detoxification pathway in rabbit and rat upper airways, although levels of AFB1-GSH and activities of glutathione transferase were significantly lower in the rat than in the rabbit and hamster. Hydrolysis of the putative AFB1-2,3-epoxide via epoxide hydrolase appeared to be the major AFB1 detoxification pathway in hamster tracheal epithelium as indicted by corresponding high tracheal microsomal AFB1-diol production and EH activity compared to rabbit and rat. Glucuronide and sulfate conjugates of AFB1 and its metabolites were formed in tracheal explant cultures from these three species, although amounts formed were minor. These results indicate that rabbit upper airway epithelium contains metabolic activity primarily involved in AFB1 activation, whereas AFB1 detoxification pathways predominante in hamster. Furthermore, the characteristics of carcinogen metabolism are not predictable based solely on airway morphology.
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PMID:Comparative biotransformation of aflatoxin B1 in mammalian airway epithelium. 189 9

The drug-metabolizing enzymes of olfactory and respiratory epithelium of cattle were determined. The data of nasal tissues were compared to those of bovine liver. Both oxidative and nonoxidative enzyme activities were investigated. Many compounds including testosterone were used as substrates for the P450-dependent monooxygenase activities. The results demonstrated that the P450 content and all the activities assayed including reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase were much higher in the olfactory than in the respiratory mucosa and for some activities (hexamethyl-phosphoramide and dimethylnitrosamine N-demethylase, aniline hydroxylase, and ethoxycoumarin O-deethylase) the values in the olfactory tissue were even markedly higher than those of liver. Also the activities of some nonoxidative enzymes such as glutathione S-transferase, uridine 5'-diphosphate (UDP)-glucuronyl-transferase, and epoxide hydrolase were higher in the olfactory than in the respiratory mucosa but lower than in liver. The results taken together suggest that the olfactory and respiratory epithelium of cattle, which contain in addition to a wide array of nonoxidative enzymes multiple forms of P450, can be useful and easily available tissues to study the biotransformation processes of odorants.
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PMID:Drug-metabolizing enzymes in liver, olfactory, and respiratory epithelium of cattle. 194 98

Both ethanol and acetone are substrates and inducers of the cytochrome P450 IIEI. This isoenzyme is induced in the perivenous region, which may explain the centrilobular damage elicited by several hepatotoxins being substrates for P450 IIE1. Here we demonstrate that induction of glutathione S-transferase after ethanol and acetone treatment is also restricted to the perivenous region, suggesting regiospecific enhancement of the transferase associated cellular defence capacity. The total glutathione peroxidase activity does not increase after the induction.
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PMID:Regioselective induction of liver glutathione transferase by ethanol and acetone. 194 85

Phenobarbital (PB) is an effective growth stimulator of hepatic hyperplastic nodules developed with diethylnitrosamine and 2-acetylaminofluorene plus partial hepatectomy (the Solt-Farber model), but it does not apparently stimulate the growth of preneoplastic lesions produced with aflatoxin B1 (AFB). Some studies have suggested a correlation between the induction of specific cytochrome P450 enzymes and the tumor promoting effects produced by repeated treatment with PB. To examine this hypothesis further, hepatic hyperplastic nodules were produced with AFB (10 ip doses of AFB, 150 micrograms/kg/day, followed by partial hepatectomy) or by a modified Solt-Farber protocol (DEN/AAF), and the effects of PB on nodule growth and expression of cytochrome(s) P450 2B1 and/or P450 2B2 (P450 2B1/2) were determined. Both treatment protocols (without PB) produced multiple, large nodules within 10-17 weeks of carcinogen administration. These nodules stained intensely for glutathione S-transferase p (GST-p; GST7-7) and gamma-glutamyl transpeptidase (GGT) and weakly for P450 2B1/2. Pentoxyphenoxazone dealkylation activity was decreased to less than 50% of the surrounding tissue levels in both types of nodules. PB treatment of animals with DEN/AAF-induced nodules greatly increased P450 2B1/2 expression in surrounding tissues, whereas most, but not all, nodules were not inducible. Pentoxyphenoxazone dealkylation was increased 31- to 35-fold in surrounding tissue, but it was increased only 2-fold in pooled nodular tissue, relative to untreated control liver. In contrast to the DEN/AAF group, immunohistochemical staining and pentoxyphenoxazone dealkylation in the AFB group demonstrated that P450 2B1/2 was equally inducible in nodular and surrounding tissues. Short-term treatment (5 days) with PB produced a 2-fold increase in the number and total area of GGT-positive nodules in the DEN/AAF group, but it had no significant effect on the number, size distribution, or total area of GGT-positive nodules in the AFB group. All large GGT-positive nodules in the DEN/AAF group were nonresponsive to induction of P450 2B1/2, whereas all of the GGT-positive nodules which were responsive to P450 2B1/2 induction by PB in this group were relatively small. The size and area of AFB-induced GGT-positive nodules was not affected by PB treatment, and P450 2B1/2 in all of these nodules was inducible by PB. Although a causal, inverse relationship between the responsiveness of nodules to PB induction of P450 2B1/2 and their reaction to PB growth stimulation cannot be firmly established, these data are consistent with such a hypothesis.
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PMID:Differential regulation of cytochrome(s) P450 2B1/2 by phenobarbital in hepatic hyperplastic nodules induced by aflatoxin B1 or diethylnitrosamine plus 2-acetylaminofluorene in male F344 rats. 194 30

Study of oxidative and non-oxidative xenobiotic-metabolizing enzymes was undertaken in microsomal and cytosolic fractions of two human livers, 10 individual and several pooled samples of human respiratory nasal mucosa obtained by surgical operation of male and female patients affected by hypertrophy of the inferior turbinates. The purity of nasal microsomes was checked by electron microscopy and marker enzyme assay. The pooled samples of respiratory nasal epithelium contained, relative to liver, a low amount of cytochrome P450 (about 25 pmol/mg protein) and associated biotransformation activities, and a low level of other components of the mixed-function oxidase system such as cytochrome b5, NADH and NADPH-cytochrome c reductase however the NADH-cytochrome b5 reductase activity was comparable to that of liver. The P450-dependent monooxygenase activities such as ethoxycoumarin O-deethylase, ethoxyresorufin O-deethylase and the dimethylnitrosamine N-demethylase were found in nearly all nasal microsomal specimens. The aniline hydroxylase and the aminopyrine or hexamethylphosphoramide N-demethylases were detected only in the pooled nasal samples. With regard to the non-oxidative enzymes, the activities of glutathione S-transferase, DT-diaphorase, epoxide hydrolase, UDP-glucuronyl-transferase, carbonyl reductase, benzaldehyde and propionaldehyde dehydrogenases, were investigated both in the individual and pooled nasal tissues and livers. These activities were similar in nasal and liver tissue, except for UDP-glucuronyltransferase which was not detected in nasal mucosa. The present findings demonstrate that the respiratory section of human nose contains a wide array of oxidative and non-oxidative enzymes, which could play a crucial role in the bioactivation or detoxication in situ of inhaled xenobiotics.
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PMID:Xenobiotic-metabolizing enzymes in human respiratory nasal mucosa. 198 28

The effects of chronic ethanol consumption on enzyme systems involved in carcinogen activation and detoxification were studied in a rat model of liver regeneration. In control rats, steady-state messenger RNAs of cytochrome P450j decreased 12 to 24 hr after partial hepatectomy but were fully recovered by 48 to 72 hr. In contrast, messenger RNA levels of cytochrome P450b and P450d did not vary significantly during that period. Steady-state messenger RNA levels for the placental form of glutathione S-transferase decreased within 30 min after partial hepatectomy but fluctuated until levels returned to normal by 48 hr. Preliminary nuclear run-on analyses suggest that the regulation of cytochrome P450j and the placental form of glutathione S-transferase messenger RNA levels involves posttranscriptional control in these animals. In ethanol-fed rats, as in controls, expression of cytochrome P450j and the placental form of glutathione S-transferase decreased transiently after partial hepatectomy. However, compared with control values, messenger RNA levels for cytochrome P450j were greater in ethanol-fed rats at each time point. Similar results were noted for placental glutathione S-transferase levels from 12 to 48 hr after partial hepatectomy. Ethanol feeding had no apparent effect on steady-state messenger RNA levels of cytochrome P450d, P450b or the multidrug-resistant gene. In both ethanol and control rats, only prehepatectomy levels of cytochrome P450 transcripts correlated with levels of the respective P450 isoenzymes. These data indicate that liver regeneration selectively decreases the steady-state messenger RNA expression of certain isoenzymes of cytochrome P450 and glutathione S-transferase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ethanol interferes with regeneration-associated changes in biotransforming enzymes: a potential mechanism underlying ethanol's carcinogenicity? 201 Jan 67

In the present study, we investigated Phase I (cytochrome P450; DT-diaphorase, DTD) and Phase II (epoxide hydrolase, EH; glutathione-S-transferases, GSTs) enzymes in normal colon from patients without colorectal adenocarcinoma and in peritumoral and tumoral tissues from patients with colorectal adenocarcinoma. No significant changes in levels of cytochrome P450IIIA4 (the only P450 detectable in this tissue), EH, GSTs and DTD activity were found between normal and peritumoral tissues. In tumoral tissue, compared with peritumoral tissues, we observed significant decreases in cytochrome P450IIIA4 (-50%, P less than 0.002) and EH (-60%, P less than 0.03), no change in DTD activity and significant increases in GST pi (+40%, P less than 0.03) and total GST activity (+30%, P less than 0.01). The numerous changes observed in tumoral tissues suggest that variations in drug-metabolizing enzyme expression in colorectal adenomatous polyps could represent pretumoral markers. Moreover, a better understanding of the expression of these enzymes in tumoral tissues would help us to choose the most appropriate colon tumor cell lines for the testing of new anti-cancer drugs.
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PMID:Drug-metabolizing enzyme expression in human normal, peritumoral and tumoral colorectal tissue samples. 202 56

To study the molecular mechanisms by which dietary lipids affect the levels of cytochrome P450 (P450) isozymes, male Sprague-Dawley rats were fed either fat-free (FF) or 20% corn oil (CO) diet in combination with one of the following three treatments: no inducer, phenobarbital (PB) and acetone. Dietary CO did not affect the constitutive level of P450IIB (PB-inducible), but it affected the induction of P450IIB by PB treatment. The induction of P450IIB by PB in the CO group as determined by 7-pentoxy-resorufin O-dealkylase activity and immunochemically detected protein level was twofold higher than that in the FF group, and this difference was also reflected in the level of mRNA for this enzyme. In contrast, dietary CO increased the constitutive level of P450IIE (ethanol-inducible) twofold as indicated by N-nitrosodimethylamine demethylase activity and immunochemically detectable protein, but it had no effect on the induction of P450IIE by acetone. The induced level of P450IIE by acetone in the CO group did not differ from that in the FF group as measured by the enzyme activity and protein level. It was demonstrated that dietary CO affects P450IIB and IIE activities by altering the concentration of the isozymes rather than by modulating their catalytic activities. In addition, dietary CO increased the microsomal testosterone 6 beta-hydroxylase activity but not 7 alpha- and 2 alpha-hydroxylase activities, suggesting an increase in P450IIIA and/or IIC13 but not in IIA1 and IIC11, respectively. Dietary CO also affected the constitutive and induced levels of glutathione S-transferase (GST) isozymes in a different manner: it increased the constitutive level of GST-B but not that of GST-A. Nevertheless, it was important for the induction of both GST-A and GST-B by PB treatment. The results suggest that lipid nutrition affects xenobiotic metabolism activities by altering constitutive and inducible levels of certain P450 and GST isozymes.
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PMID:Roles of dietary corn oil in the regulation of cytochromes P450 and glutathione S-transferases in rat liver. 226 16


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