The role of epoxidation and electrophile-responsive element-regulated gene transcription in the potentially beneficial and harmful effects of the coffee components cafestol and kahweol

S.T.J. van Cruchten, L.H.J. de Haan, P.P.J. Mulder, C. Kunne, M.V. Boekschoten, M.B. Katan, J.M.M.J.G. Aarts, R.F. Witkamp

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Abstract

Cafestol and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety, we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH) conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other toxic or carcinogenic compounds
Original languageEnglish
Pages (from-to)757-763
JournalJournal of Nutritional Biochemistry
Volume21
Issue number8
DOIs
Publication statusPublished - 2010

Fingerprint

Coffee
Epoxidation
Transcription
Genes
Aflatoxin B1
kahweol
cafestol
Diterpenes
Nucleic Acid Regulatory Sequences
Poisons
Epoxy Compounds
Glucuronides
Nutrition
Biotransformation
Bile Ducts
Luciferases
Reporter Genes
Ducts
Glutathione
Hepatocellular Carcinoma

Keywords

  • cholesterol-raising factor
  • nf-kappa-b
  • rat-liver
  • glutathione transferase
  • normolipidemic subjects
  • diterpenes cafestol
  • boiled coffee
  • serum-lipids
  • cancer-risk
  • metabolism

Cite this

@article{89ad567bdfcf43d38ef3d84c45a72cf2,
title = "The role of epoxidation and electrophile-responsive element-regulated gene transcription in the potentially beneficial and harmful effects of the coffee components cafestol and kahweol",
abstract = "Cafestol and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety, we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH) conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other toxic or carcinogenic compounds",
keywords = "cholesterol-raising factor, nf-kappa-b, rat-liver, glutathione transferase, normolipidemic subjects, diterpenes cafestol, boiled coffee, serum-lipids, cancer-risk, metabolism",
author = "{van Cruchten}, S.T.J. and {de Haan}, L.H.J. and P.P.J. Mulder and C. Kunne and M.V. Boekschoten and M.B. Katan and J.M.M.J.G. Aarts and R.F. Witkamp",
year = "2010",
doi = "10.1016/j.jnutbio.2009.05.001",
language = "English",
volume = "21",
pages = "757--763",
journal = "Journal of Nutritional Biochemistry",
issn = "0955-2863",
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number = "8",

}

TY - JOUR

T1 - The role of epoxidation and electrophile-responsive element-regulated gene transcription in the potentially beneficial and harmful effects of the coffee components cafestol and kahweol

AU - van Cruchten, S.T.J.

AU - de Haan, L.H.J.

AU - Mulder, P.P.J.

AU - Kunne, C.

AU - Boekschoten, M.V.

AU - Katan, M.B.

AU - Aarts, J.M.M.J.G.

AU - Witkamp, R.F.

PY - 2010

Y1 - 2010

N2 - Cafestol and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety, we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH) conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other toxic or carcinogenic compounds

AB - Cafestol and kahweol are diterpene compounds present in unfiltered coffees. Cafestol is known as the most potent cholesterol-raising agent that may be present in the human diet. Remarkably, the mechanisms behind this effect have only been partly resolved so far. Even less is known about the metabolic fate of cafestol and kahweol. From the structure of cafestol, carrying a furan moiety, we hypothesized that epoxidation may not only be an important biotransformation route but that this also plays a role in its effects found. In bile duct-cannulated mice, dosed with cafestol, we were able to demonstrate the presence of epoxy-glutathione (GSH) conjugates, GSH conjugates and glucuronide conjugates. In addition, it was shown that cafestol was able to induce an electrophile-responsive element (EpRE). Using a murine hepatoma cell line with a luciferase reporter gene under control of an EpRE from the human NQO1 regulatory region, we also found that metabolic activation by CYP450 enzymes is needed for EpRE induction. Furthermore, raising intracellular GSH resulted in a decrease in EpRE-mediated gene induction, whereas lowering intracellular GSH levels increased EpRE-mediated gene induction. In conclusion, evidence suggests that cafestol induces EpRE, apparently via a bioactivation process that possibly involves epoxidation of the furan ring. The epoxides themselves appear subject to conjugation with GSH. The effects on EpRE can also explain the induction of GSH which seems to be involved in the reported beneficial effects of cafestol, for example, when administered with aflatoxin B1 or other toxic or carcinogenic compounds

KW - cholesterol-raising factor

KW - nf-kappa-b

KW - rat-liver

KW - glutathione transferase

KW - normolipidemic subjects

KW - diterpenes cafestol

KW - boiled coffee

KW - serum-lipids

KW - cancer-risk

KW - metabolism

U2 - 10.1016/j.jnutbio.2009.05.001

DO - 10.1016/j.jnutbio.2009.05.001

M3 - Article

VL - 21

SP - 757

EP - 763

JO - Journal of Nutritional Biochemistry

JF - Journal of Nutritional Biochemistry

SN - 0955-2863

IS - 8

ER -