May 17, 2002
Vitamin D May Be Crucial in Preventing Colon Cancer
New studies by researchers at the Howard Hughes Medical Institute
indicate that vitamin D protects against colon cancer by helping to
detoxify cancer-triggering chemicals that are released during the
digestion of high-fat foods.
The discovery, which was made by a team of researchers that included
Howard Hughes Medical Institute (HHMI) investigators David
J. Mangelsdorf at the University of Texas Southwestern Medical
Center and Ronald M.
Evans of The Salk Institute and colleagues at the University of
Arizona, was reported in the May 17, 2002, issue of the journal
Science.
“Our findings suggest a new look at the relationship between nutrition and cancer, particularly how vitamin D protects against colon cancer.”
David J. Mangelsdorf
The studies show that a specific type of bile acid, called
lithocholic acid (LCA), which is a known carcinogen, activates the
vitamin D receptor. When the vitamin D receptor is switched on, it
triggers other proteins that detoxify the bile acid.
The research suggests that a drug that acts like vitamin D might
help in preventing colon cancer by turning on the vitamin D receptor
and clearing LCA from the body. One obstacle that must be overcome,
however, is that high intake of vitamin D or drugs that mimic vitamin D
can lead to dangerous levels of calcium in the blood.
Colon cancer expert Bert
Vogelstein, an HHMI investigator at the Sidney Kimmel Comprehensive
Cancer Center at The Johns Hopkins University, said, “these
studies provide important new clues to the relationship between vitamin
D, bile acids, and colorectal cancer, and they have significant
implications for colorectal cancer prevention in the future.”
Mangelsdorf, Evans and their colleagues studied the effects of the
bile acid, LCA, which is produced as a by-product when intestinal
bacteria digest primary bile acids produced in the liver. Primary bile
acids help the body digest dietary fats. The experiments showed that
LCA activates the vitamin D receptor, which then activates additional
genes that help detoxify LCA.
“There’s an abundance of epidemiologic data, as well as
some scientific data, suggesting a correlation between high-fat diets,
bile acids such as LCA, and colon cancer,” said Mangelsdorf.
“But there has been no causal link, which has been one of the
frustrating aspects of trying to understand the relationship between
our Western-style high-fat diet and colon cancer.
Although it had been shown that vitamin D can prevent colon cancer
in rats treated with LCA, and that humans with defective vitamin D
signaling pathways have a higher incidence of colon cancer, it remained
unclear how vitamin D actually prevents colon cancer. A reasonable
theory, according to Mangelsdorf, was that vitamin D and LCA both
triggered a biochemical pathway involved in detoxifying LCA. The best
candidate was a pathway that involved the vitamin D receptor.
In one set of studies, the researchers showed that the vitamin D
receptor strongly binds to LCA. But the researchers also needed to
demonstrate that binding LCA actually activates a key gene, called
CYP3A, which triggers the cell’s detoxification machinery.
The scientists attached a “reporter” gene to CYP3A
in human cells in culture, so they could detect whether the
CYP3A gene was switched on when LCA attached to the vitamin D
receptor.
“Other investigators had published data showing that vitamin D
could switch on this gene, but it was a big surprise that LCA could do
it also,” said Mangelsdorf. The scientists also performed
experiments in mice, in which they found that feeding the animals LCA
led to the activation of certain vitamin-D-receptor target genes.
The scientists ultimately demonstrated that the vitamin D receptor
was the only receptor activated by LCA. “We showed that in our
knockout mice, LCA still induces the expression of CYP3A, just
like vitamin D does,” said Mangelsdorf. “So this crucial
experiment demonstrated that vitamin D and LCA were not working through
another receptor but through the vitamin D receptor.”
According to Mangelsdorf, the findings suggest that the vitamin D
receptor acts as a sensor for the toxic chemical LCA. Other receptors
in the body can sense dietary fats and other foreign chemicals, and
serve to “alert” the body to begin detoxification when the
chemicals reach dangerous levels.
“Our findings suggest a new look at the relationship between
nutrition and cancer, particularly how vitamin D protects against colon
cancer,” he said. “One problem with using vitamin D as a
protective drug has always been that it produces hypercalcemia. But now
we know that there’s another endogenous compound, LCA, that can
also attach to the receptor, this suggests that we can develop
protective drugs that don’t produce hypercalcemia, but do
activate the detoxification pathway.”
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