Effects of synthetic and natural in vivo inhibitors of ß- glucuronidase on azoxymethane-induced colon carcinogenesis in rats

Nanae Morita, Zbigniew Walaszek, Tatsuya Kinjo, Tadashi Nishimaki, Margaret Hanausek, Thomas J. Slaga, Hideki Mori, Naoki Yoshimi

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

D-Glucaric acid is a non-toxic natural compound found in many fruits and vegetables. Our previous studies have shown that the ß-glucuronidase inhibitor D-glucaro-1,4-lactone, an active metabolite of D-glucaric acid, inhibits chemically-induced tumorigenesis in rodents. D-Glucaro-1,4-lactone has a synthetic precursor, 2,5-di-O-acetyl-Dglucaro-1,4:6,3-dilactone or aceglatone (ACE), known as a postoperative prophylactic agent, and a natural precursor, D-glucurono-γ-lactone (GL). In the present study, we first examined the effect of ACE on the initiation phase of rat colon carcinogenesis induced by 15 mg/kg azoxymethane (AOM) administered 3 times by subcutaneous (s.c.) injection at weeks 1, 2, and 3 of a 5-week short-term experiment. ACE (0.5 or 2%) was administered as a dietary supplement for 5 weeks. At 5 weeks after the initiation of treatment, the formation of aberrant crypt foci (ACF) in the rat groups treated with AOM plus a 0.5 or 2% ACE diet was significantly reduced by 48.6 and 55.3%, respectively, compared to the group administered AOM alone. In a previous study, 0.5 and 2% ACE diets dispensed during AOM treatment had a tendency to decrease AOM-induced colonic tumor incidence. In the present longterm 36-week colon tumorigenesis experiment, GL (0.5 or 2%) administered via the diet during the initiation phase (starting 1 week before the first dose of AOM and ending 1 week after the 3rd dose) did not have any significant effects on tumor incidence. On the other hand, continued post-initiation treatment with ACE (0.5 and 2%) markedly reduced colonic tumor incidence by 70 and 80%, respectively. GL was effective to a similar extent (70% inhibition), but only at a concentration of 2%. We conclude that ACE inhibits the initiation and post-initiation stages of AOM-induced colon carcinogenesis, while GL affects only the post-initiation stages.

Original languageEnglish (US)
Pages (from-to)741-746
Number of pages6
JournalMolecular Medicine Reports
Volume1
Issue number5
DOIs
Publication statusPublished - Dec 1 2008

    Fingerprint

Keywords

  • 2,5-di-O-acetyl-D-glucaro-1,4:6,3-dilactone
  • Azoxymethane
  • Colon carcinogenesis
  • D-glucurono-γ-lactone
  • ß-glucuronidase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

Cite this