Helenanolide type sesquiterpene lactones. Part 5: The role of glutathione addition under physiological conditions

Schmidt, Thomas J.; Lyß, Guido; Pahl, Heike L.; Merfort, Irmgard

doi:10.1016/s0968-0896(99)00234-5

Cited by 77 publications

(62 citation statements)

References 14 publications

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“…12B). Based on these observations, we speculated that elevated GSH levels might compete with essential Cys residues either of NF-B subunits (56) or other redox regulators relevant for NF-B function for interaction with SFN. At conditions of low GSH, SFN would predominantly interact with these factors and exert a stronger inhibitory effect, whereas higher GSH concentrations would render it less accessible for other reaction partners.…”

Section: Discussionmentioning

confidence: 98%

Nuclear Factor κB Is a Molecular Target for Sulforaphane-mediated Anti-inflammatory Mechanisms

Heiss

Herhaus

Klimo

et al. 2001

Journal of Biological Chemistry

581

421

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Section: Discussionmentioning

confidence: 98%

Nuclear Factor κB Is a Molecular Target for Sulforaphane-mediated Anti-inflammatory Mechanisms

Heiss

Herhaus

Klimo

et al. 2001

Journal of Biological Chemistry

581

421

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“…3B. These electrophilic groups are known to undergo Michael-type addition reactions with nucleophiles, such as the thiol groups of cysteine residues, leading to the formation of covalent adducts (33,34). For example, helenalin and helenalin acetate have been shown to inhibit the DNA binding activity of transcription factor NF-B by covalent modification of Cys-38 of the p65 subunit of NF-B (27,28).…”

Section: The Presence Of Reactive Groups Is Not Sufficient To Explainmentioning

confidence: 99%

Helenalin Acetate, a Natural Sesquiterpene Lactone with Anti-inflammatory and Anti-cancer Activity, Disrupts the Cooperation of CCAAT Box/Enhancer-binding Protein β (C/EBPβ) and Co-activator p300

Jakobs

Steinmann

Henrich

et al. 2016

Journal of Biological Chemistry

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Edited by Joel GottesfeldRecent work has demonstrated pro-oncogenic functions of the transcription factor CCAAT box/enhancer-binding protein ␤ (C/EBP␤) in various tumors, implicating C/EBP␤ as an interesting target for the development of small-molecule inhibitors. We have previously discovered that the sesquiterpene lactone helenalin acetate, a natural compound known to inhibit NF-B, is a potent C/EBP␤ inhibitor. We have now examined the inhibitory mechanism of helenalin acetate in more detail. We demonstrate that helenalin acetate is a significantly more potent inhibitor of C/EBP␤ than of NF-B. Our work shows that helenalin acetate inhibits C/EBP␤ by binding to the N-terminal part of C/EBP␤, thereby disrupting the cooperation of C/EBP␤ with the co-activator p300. C/EBP␤ is expressed in several isoforms from alternative translational start codons. We have previously demonstrated that helenalin acetate selectively inhibits only the full-length (liver-enriched activating protein* (LAP*)) isoform but not the slightly shorter (LAP) isoform. Consistent with this, helenalin acetate binds to the LAP* but not to the LAP isoform, explaining why its inhibitory activity is selective for LAP*. Although helenalin acetate contains reactive groups that are able to interact covalently with cysteine residues, as exemplified by its effect on NF-B, the inhibition of C/EBP␤ by helenalin acetate is not due to irreversible reaction with cysteine residues of C/EBP␤. In summary, helenalin acetate is the first highly active small-molecule C/EBP␤ inhibitor that inhibits C/EBP␤ by a direct binding mechanism. Its selectivity for the LAP* isoform also makes helenalin acetate an interesting tool to dissect the functions of the LAP* and LAP isoforms.

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“…Kavalactones may cause hepatic stress, if not mediated by glutathione, and are usually metabolized in the liver by enzymes called lactone hydrolases (Schmidt et al, 1999). It can also be demonstrated in vitro that kavalactones combine with glutathione in a pH dependant reaction by placing a mixture of kavalactones and glutathione in a test tube and adding 0.1M of sodium hydroxide to adjust the pH to between 7 and 10.…”

Section: Importance Of Glutathione In Kava Extractsmentioning

confidence: 99%

“…There has been relevant work on a related group of compounds, sesquiterpene lactones. It has been demonstrated that sesquiterpene lactones react with the sulfide group on the glutathione molecule in a reversible pH dependent reaction (Schmidt et al, 1999). The binding of the sesquiterpene lactones to the glutathione molecule allows for faster clearance by the lactone hydrolases present in the hepatocytes (Schmidt et al, 2001).…”

Section: Importance Of Glutathione In Kava Extractsmentioning

confidence: 99%

Kava—the Unfolding Story: Report on a Work-in-Progress

Denham

McIntyre²,

Whitehouse

2002

The Journal of Alternative and Complementary Medicine

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Helenanolide type sesquiterpene lactones. Part 5: The role of glutathione addition under physiological conditions

Cited by 77 publications

References 14 publications

Nuclear Factor κB Is a Molecular Target for Sulforaphane-mediated Anti-inflammatory Mechanisms

Nuclear Factor κB Is a Molecular Target for Sulforaphane-mediated Anti-inflammatory Mechanisms

Helenalin Acetate, a Natural Sesquiterpene Lactone with Anti-inflammatory and Anti-cancer Activity, Disrupts the Cooperation of CCAAT Box/Enhancer-binding Protein β (C/EBPβ) and Co-activator p300

Kava—the Unfolding Story: Report on a Work-in-Progress

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