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
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.