New studies by researchers from the Howard Hughes Medical Institute indicate that vitamin D protects against colon cancer because it helps in the detoxification of chemicals that trigger cancer and that are released during digestion of high fat foods.
The discovery, which was conducted by a research team that included researchers from the Howard Hughes Medical Institute David J. Mangelsdorf, Medical Center of Texas Southwestern University, and Ronald M. Evans of the Salk Institute and colleagues at the University of Arizona, was published in the issue of May 17, 2002, issue of Science.
"Our results suggest a new way of looking at the relationship between nutrition and cancer, particularly on how vitamin D protects us from colon cancer."
David J. Mangelsdorf
Studies show that a specific type of bile acid called lithocholic acid (CLA), a known carcinogen, activates the receptor for vitamin D.
When you activate the vitamin D receptor, this in turn activates other proteins that bile acid detoxification.
Research suggests that a drug that acts like vitamin D might help prevent colon cancer by activating the vitamin D receptor and eliminate body ALC. One obstacle to be overcome, however, is that high intake of vitamin D or drugs that mimic the activity of vitamin D can lead to dangerous blood levels of calcium.
The colon cancer expert, Bert Vogelstein, an HHMI investigator at the Sidney Kimmel Cancer Center comprenhensive Johns Hopkins University said: "These studies provide important new clues about the relationship between vitamin D, bile acids and colorectal cancer and have significant implications for the prevention of colorectal cancer in the future. "
Mangelsdorf, Evans and colleagues studied the effects of bile acid, LCA, which is produced as a byproduct when intestinal bacteria digest the primary bile acids are produced in the liver.
The discovery, which was conducted by a research team that included researchers from the Howard Hughes Medical Institute David J. Mangelsdorf, Medical Center of Texas Southwestern University, and Ronald M. Evans of the Salk Institute and colleagues at the University of Arizona, was published in the issue of May 17, 2002, issue of Science.
"Our results suggest a new way of looking at the relationship between nutrition and cancer, particularly on how vitamin D protects us from colon cancer."
David J. Mangelsdorf
Studies show that a specific type of bile acid called lithocholic acid (CLA), a known carcinogen, activates the receptor for vitamin D.
When you activate the vitamin D receptor, this in turn activates other proteins that bile acid detoxification.
Research suggests that a drug that acts like vitamin D might help prevent colon cancer by activating the vitamin D receptor and eliminate body ALC. One obstacle to be overcome, however, is that high intake of vitamin D or drugs that mimic the activity of vitamin D can lead to dangerous blood levels of calcium.
The colon cancer expert, Bert Vogelstein, an HHMI investigator at the Sidney Kimmel Cancer Center comprenhensive Johns Hopkins University said: "These studies provide important new clues about the relationship between vitamin D, bile acids and colorectal cancer and have significant implications for the prevention of colorectal cancer in the future. "
Mangelsdorf, Evans and colleagues studied the effects of bile acid, LCA, which is produced as a byproduct when intestinal bacteria digest the primary bile acids are produced in the liver.
Primary bile acids help the body digest fats in the diet. The experiments showed that CLA activates the vitamin D receptor, which then activates additional genes that help detoxify the FTA.
"There is a lot of epidemiological data and certain scientific data, which were to suggest a correlation between diets high grade tenor, bile acids, such as the FTA, and colon cancer," said Mangelsdorf.
"But there have been causal links, it has been frustrating trying to understand the relationship between our Western-style diet rich in fat and colon cancer."
Although it was shown that vitamin D could prevent colon cancer in rats treated with LAC, and that human beings signaling pathways defective vitamin D have a higher incidence of colon cancer, it remained unclear how vitamin D prevented colon cancer. A reasonable theory, according to Mangelsdorf, was that vitamin D and CLA triggered a biochemical pathway involved in the detoxification of the FTA. The best candidate was a way to involve the receptor for vitamin D.
In a series of studies, researchers showed that the vitamin D receptor binds tightly to the FTA.
But the researchers also needed to demonstrate that ALC binding actually activates a key gene, called CYP3A, which activates the detoxification machinery of the cell.
The scientists attached a "reporter" gene CYP3A in cultured human cells, to detect whether the CYP3A gene was activated when the ALC joined the vitamin D receptor
"Other investigators had published data showing that vitamin D could activate this gene, but it was a great surprise that the FTA could also do it," said Mangelsdorf. The scientists also conducted experiments on mice, which found that feeding CLA to animals produced the activation of certain genes that are targets of vitamin D receptor
The scientists showed, ultimately, that the vitamin D receptor was the only receptor activated by the FTA. "We showed that in our knock-out mice, CLA can still induce the expression of CYP3A, like vitamin D," said Mangelsdorf. "So this crucial experiment showed that vitamin D and CLA did not work through another receptor, but did so through the vitamin D receptor."
According to Mangelsdorf, the results suggest that vitamin D receptor acts as a sensor for toxic chemical LAC. Other receptors in the body can detect fat from the diet and other foreign chemicals, and can serve to "alert" the body to begin detoxification when the chemicals reach dangerous levels.
"Our results suggest a new way of looking at the relationship between nutrition and cancer, particularly on how vitamin D protects us from colon cancer," he said. "One problem with the use of vitamin D as a protective drug, has always been that it causes hypercalcemia.
"There is a lot of epidemiological data and certain scientific data, which were to suggest a correlation between diets high grade tenor, bile acids, such as the FTA, and colon cancer," said Mangelsdorf.
"But there have been causal links, it has been frustrating trying to understand the relationship between our Western-style diet rich in fat and colon cancer."
Although it was shown that vitamin D could prevent colon cancer in rats treated with LAC, and that human beings signaling pathways defective vitamin D have a higher incidence of colon cancer, it remained unclear how vitamin D prevented colon cancer. A reasonable theory, according to Mangelsdorf, was that vitamin D and CLA triggered a biochemical pathway involved in the detoxification of the FTA. The best candidate was a way to involve the receptor for vitamin D.
In a series of studies, researchers showed that the vitamin D receptor binds tightly to the FTA.
But the researchers also needed to demonstrate that ALC binding actually activates a key gene, called CYP3A, which activates the detoxification machinery of the cell.
The scientists attached a "reporter" gene CYP3A in cultured human cells, to detect whether the CYP3A gene was activated when the ALC joined the vitamin D receptor
"Other investigators had published data showing that vitamin D could activate this gene, but it was a great surprise that the FTA could also do it," said Mangelsdorf. The scientists also conducted experiments on mice, which found that feeding CLA to animals produced the activation of certain genes that are targets of vitamin D receptor
The scientists showed, ultimately, that the vitamin D receptor was the only receptor activated by the FTA. "We showed that in our knock-out mice, CLA can still induce the expression of CYP3A, like vitamin D," said Mangelsdorf. "So this crucial experiment showed that vitamin D and CLA did not work through another receptor, but did so through the vitamin D receptor."
According to Mangelsdorf, the results suggest that vitamin D receptor acts as a sensor for toxic chemical LAC. Other receptors in the body can detect fat from the diet and other foreign chemicals, and can serve to "alert" the body to begin detoxification when the chemicals reach dangerous levels.
"Our results suggest a new way of looking at the relationship between nutrition and cancer, particularly on how vitamin D protects us from colon cancer," he said. "One problem with the use of vitamin D as a protective drug, has always been that it causes hypercalcemia.
But now we know that there is another endogenous compound, the FTA, which can also bind to the receptor, we can develop protective drugs that do not cause hypercalcemia, but to activate the detoxification pathway. "
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