Ceramide-beta-D-glucuronide: Synthesis, digestion, and suppression of early markers of colon carcinogenesis

Citation
Em. Schmelz et al., Ceramide-beta-D-glucuronide: Synthesis, digestion, and suppression of early markers of colon carcinogenesis, CANCER RES, 59(22), 1999, pp. 5768-5772
Citations number
38
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
CANCER RESEARCH
ISSN journal
00085472 → ACNP
Volume
59
Issue
22
Year of publication
1999
Pages
5768 - 5772
Database
ISI
SICI code
0008-5472(19991115)59:22<5768:CSDASO>2.0.ZU;2-1
Abstract
Dietary sphingolipids inhibit chemically induced colon cancer in mice. The most Likely mediators of this effect are the metabolites ceramide (Cer) and sphingosine, which induce growth arrest and apoptosis in transformed cells . Sphingolipids are digested in both the upper and the lower intestine; the refore, a more colon-specific method of delivery of sphingolipids might be useful. A Cer analogue with a D-glucuronic acid attached at the primary hyd roxyl of N-palmitoyl-D-sphingosine (Cer- beta-glucuronide) was synthesized and evaluated as a substrate for Escherichia coli beta-glucuronidase and co lonic digestion, as wed as for suppression of early events in colon carcino genesis in CF1 mice treated with 1,2-dimethylhydrazine. Purified beta-glucu ronidase (EC 3.2.1.31) and colonic segments las a source of colonic enzymes and microflora) hydrolyzed Cer-beta-glucuronide to release Cer, as analyze d by tandem mass spectrometry. More than 75% of the Cer-beta-glucuronide wa s cleaved in an 8-11 incubation with the colonic segments. When Cer-beta-gl ucuronide tvas administered for 1 weeks as 0.925% and 0.1% of the diet (AIN 76A) to 1,2-dimethylhydrazine-treated mice, there were significant reducti ons in colonic cell proliferation, as determined by in vivo BrdUrd incorpor ation, and in the appearance of aberrant crypt foci. The effect of dietary Cer-beta-glucuronide on aberrant crypt foci correlated significantly with t he length of the colon, which suggests that Cer-beta-glucuronide was most e ffective when there was a larger compartment for digestion. Thus, synthetic sphingolipids that target the colon for the release of the bioactive backb ones offer a promising approach to colon cancer prevention.