5,287 research outputs found
Induction of epoxide hydrolase and glucuronosyl transferase by isothiocyanates and intact glucosinolates in precision-cut rat liver slices: Importance of side-chain substituent and chirality
No full textThe potential of three isothiocyanates, namely R,S-sulforaphane, erucin and phenethyl isothiocyanate, of two naturally occurring glucosinolates, namely glucoerucin and glucoraphanin, and of the enantiomers of sulforaphane to modulate glucuronosyl transferase and epoxide hydrolase, two major carcinogen-metabolising enzyme systems, was investigated in precision-cut rat liver slices. Following exposure of the slices to the isothiocyanates (0-25 Î1⁄4M), erucin and phenethyl isothiocyanate, but not R,S-sulforaphane, elevated glucuronosyl transferase and epoxide hydrolase activities and expression, determined immunologically. Of the two enantiomers of sulforaphane, the R-enantiomer enhanced, whereas the S-enantiomer impaired, glucuronosyl transferase activity and only the former increased protein expression; furthermore, R-sulforaphane was more effective than the S-enantiomer in up-regulating microsomal epoxide hydrolase. When precision-cut rat liver slices were exposed to the same concentrations of glucoerucin and glucoraphanin, both glucosinolates caused a marked increase in the activity and expression of the microsomal epoxide hydrolase but had no effect on glucuronosyl transferase activity. It may be inferred that the ability of isothiocyanates to enhance hepatic microsomal epoxide hydrolase and glucuronosyl transferase activities is dependent on the nature of the side chain. Moreover, in the case of sulforaphane, the naturally occurring R-enantiomer increased both activities, whereas, in contrast, activities were impaired in the case of the S-enantiomer. Finally, intact glucosinolates are potent inducers of epoxide hydrolase and can thus contribute directly to the chemopreventive potential associated with cruciferous vegetable consumption. © 2010 Springer-Verlag
Characterization of the temporal induction of hepatic xenobiotic- metabolizing enzymes by glucosinolates and isothiocyanates: Requirement for at least a 6 h exposure to elicit complete induction profile
No full textA mechanism of action of chemopreventive glucosinolates/isothiocyanates, established largely in vitro, is to modulate carcinogen-metabolizing enzymes. Extrapolation in vivo involves relating in vitro concentrations to plasma/tissue concentrations attained in vivo, thus assuming that even transient exposure modulates enzyme activity. To test this hypothesis, precision-cut rat liver slices were incubated with glucosinolates for up to 24 h, and the O-dealkylation of methoxyresorufin and ethoxyresorufin was determined; increased activities were observed only at incubations of at least 6 h. To evaluate phase II enzymes, isothiocyanates, namely, sulforaphane, erucin, and phenethyl isothiocyanate, were similarly incubated; quinone reductase increased after incubation for 6 h or longer. When glutathione S-transferase was monitored, the phenethyl isothiocyanate-manifested rise necessitated at least a 6 h incubation, whereas in the case of sulforaphane and erucin, the activity was elevated after only 2 h. It is inferred that a rise in carcinogen-metabolizing enzymes by glucosinolates/isothiocyanates necessitates tissue exposure of at least 6 h. © 2012 American Chemical Society
The natural chemopreventive phytochemical R-sulforaphane is a far more potent inducer of the carcinogen-detoxifying enzyme systems in rat liver and lung than the S-isomer
No full textThe natural chemopreventive phytochemical R-sulforaphane is a far more potent inducer of the carcinogen-detoxifying enzyme systems in rat liver and lung than the S-isomer
No full textThe chemopreventive potential of dietary glucosinolates
No full textDietary intake of a glucosinolate-rich Daikon extract (glucoraphasatin and glucoraphenin) elevated rat hepatic dealkylations of methoxy-, ethoxy-, pentoxyresorufin and benzyloxyquinoline, accompanied by increased expression of CYPl and CYP3A2 apoprotein levels. A marked induction of glutathione S- transferase and quinone reductase activities in liver was evident, as well as of glucuronosyl transferase and epoxide hydrolase activities and expression, but only at higher doses. Lung enzymes were not altered by the same treatment. In precision-cut rat liver slices glucoraphasatin caused a marked increase in epoxide hydrolase activity. Addition of myrosinase to form the isothiocyanate led to a marked rise in glutathione S-transferase, quinone reductase and epoxide hydrolase activities and expression. Incubation of precision-cut rat liver slices with intact glucosinolates (glucoerucin and glucoraphanin) enhanced the O-dealkylations of methoxy- and ethoxyresorufin and elevated CYPl apoprotein levels; similar effects were observed in lung slices. Both glucosinolates increased hepatic epoxide hydrolase, glutathione S-transferase and quinone reductase activities. Studies on the temporal induction of carcinogen-metabolising enzyme systems by glucosinolates and isothiocyanates in precision-cut rat liver slices indicated that a six- hour tissue exposure was required for induction of all enzymes to be manifested. The potential of the naturally-occurring R-sulforaphane to up-regulate carcinogen- metabolising enzyme in precision-cut rat liver slices and FAO cells was compared to that of S-sulforaphane; R -sulforaphane was superior in modulating these enzyme systems in both systems. Using the CALUX assay it was established that phenethyl isothiocyanate, erucin and sulforaphane were poor ligands to the Ah receptor. However, they effectively antagonised, III a non-competitive manner, the activation of the receptor by benzo[a]pyrene. Further studies revealed that sulforaphane could prevent and reverse the activation of the Ah receptor by benzo[a]pyrene.EThOS - Electronic Theses Online ServiceGBUnited Kingdo
The Chemopreventive Potential of Dietary Glucosinolates.
No full textDietary intake of a glucosinolate-rich Daikon extract (glucoraphasatin and glucoraphenin) elevated rat hepatic dealkylations of methoxy-, ethoxy-, pentoxyresorufin and benzyloxyquinoline, accompanied by increased expression of CYPl and CYP3A2 apoprotein levels. A marked induction of glutathione S- transferase and quinone reductase activities in liver was evident, as well as of glucuronosyl transferase and epoxide hydrolase activities and expression, but only at higher doses. Lung enzymes were not altered by the same treatment. In precision-cut rat liver slices glucoraphasatin caused a marked increase in epoxide hydrolase activity. Addition of myrosinase to form the isothiocyanate led to a marked rise in glutathione S-transferase, quinone reductase and epoxide hydrolase activities and expression. Incubation of precision-cut rat liver slices with intact glucosinolates (glucoerucin and glucoraphanin) enhanced the O-dealkylations of methoxy- and ethoxyresorufin and elevated CYPl apoprotein levels; similar effects were observed in lung slices. Both glucosinolates increased hepatic epoxide hydrolase, glutathione S-transferase and quinone reductase activities. Studies on the temporal induction of carcinogen-metabolising enzyme systems by glucosinolates and isothiocyanates in precision-cut rat liver slices indicated that a six- hour tissue exposure was required for induction of all enzymes to be manifested. The potential of the naturally-occurring R-sulforaphane to up-regulate carcinogen- metabolising enzyme in precision-cut rat liver slices and FAO cells was compared to that of S-sulforaphane; R -sulforaphane was superior in modulating these enzyme systems in both systems. Using the CALUX assay it was established that phenethyl isothiocyanate, erucin and sulforaphane were poor ligands to the Ah receptor. However, they effectively antagonised, III a non-competitive manner, the activation of the receptor by benzo[a]pyrene. Further studies revealed that sulforaphane could prevent and reverse the activation of the Ah receptor by benzo[a]pyrene
Ipilimumab in pretreated metastatic uveal melanoma patients: safety and clinical efficacy
No full text
"And they fastened his body to the wall of Beth-shan" (1 Sm 31, 10). The problem of a suicide in the Old Testament. This paper addresses a multi-faceted, intriguing issue of suicide in the Bible, especially in Jewish and ancient tradition. The author aims to show all cases of suicide in the Old Testament (Abimelech, Samson, King Saul and his armor-bearer, Ahithophel, Zimri, Ptolemy Macron, Razis), focusing on a theological, linguistic and cultural analysis of selected biblical excerpts. In addition, there are many of suicide prevention in the Bible in which God’s intervention prevented the accomplishment of suicidal behavior (Moses, David, Elijah, Job, Jeremiah, Jonah). Suicide in the Bible occurs for a variety of complicated, ambiguous reasons, including intense personal guilt, sense of hopelessness, human inclination to despair or tremendous personal loss. The Bible nowhere proscribes suicide distinctly, and the question of self-killing in Hebrew Scriptures is a still live dilemma
Induction of epoxide hydrolase and glucuronosyl transferase by isothiocyanates and intact glucosinolates in precision-cut rat liver slices: importance of side-chain substituent and chirality.
No full textThe potential of three isothiocyanates, namely R,S-sulforaphane, erucin and phenethyl isothiocyanate, of two naturally occurring glucosinolates, namely glucoerucin and glucoraphanin, and of the enantiomers of sulforaphane to modulate glucuronosyl transferase and epoxide hydrolase, two major carcinogen-metabolising enzyme systems, was investigated in precision-cut rat liver slices. Following exposure of the slices to the isothiocyanates (0-25 μM), erucin and phenethyl isothiocyanate, but not R,S-sulforaphane, elevated glucuronosyl transferase and epoxide hydrolase activities and expression, determined immunologically. Of the two enantiomers of sulforaphane, the R-enantiomer enhanced, whereas the S-enantiomer impaired, glucuronosyl transferase activity and only the former increased protein expression; furthermore, R-sulforaphane was more effective than the S-enantiomer in up-regulating microsomal epoxide hydrolase. When precision-cut rat liver slices were exposed to the same concentrations of glucoerucin and glucoraphanin, both glucosinolates caused a marked increase in the activity and expression of the microsomal epoxide hydrolase but had no effect on glucuronosyl transferase activity. It may be inferred that the ability of isothiocyanates to enhance hepatic microsomal epoxide hydrolase and glucuronosyl transferase activities is dependent on the nature of the side chain. Moreover, in the case of sulforaphane, the naturally occurring R-enantiomer increased both activities, whereas, in contrast, activities were impaired in the case of the S-enantiomer. Finally, intact glucosinolates are potent inducers of epoxide hydrolase and can thus contribute directly to the chemopreventive potential associated with cruciferous vegetable consumption
The naturally occurring aliphatic isothiocyanates sulforaphane and erucin are weak agonists but potent non-competitive antagonists of the aryl hydrocarbon receptor.
No full textAs the Ah receptor target gene products play a critical role in chemical carcinogenesis, antagonists are considered as potential chemopreventive agents. It is demonstrated in this paper that the isothiocyanates R,S-sulforaphane and erucin are non-competitive antagonists of the aryl hydrocarbon (Ah) receptor. Both isothiocyanates were poor agonists for the receptor and elevated CYP1A1 mRNA levels only modestly when incubated with precision-cut rat liver slices. In contrast, the classical Ah receptor agonist benzo[a]pyrene was a potent inducer of CYP1A1 mRNA levels, with this effect being effectively antagonized by the two isothiocyanates. In further studies, it was demonstrated that R,S-sulforaphane could both prevent the interaction of and displace already bound benzo[a]pyrene from the Ah receptor, but no concentration dependency was observed with respect to the isothiocyanate. Both erucin and R,S-sulforaphane antagonized the benzo[a]pyrene-mediated increase in the CYP1A-mediated O-deethylation of ethoxyresorufin in rat precision-cut liver slices. Of the two isomers of R,S-sulforaphane, the naturally occurring R-isomer was more effective than the S-isomer in antagonizing the activation of the Ah receptor by benzo[a]pyrene. Antagonism of the Ah receptor may be a major contributor to the established chemoprevention of aliphatic isothiocyanates
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