Epidemiologic studies suggest that nutritional
phytoestrogens contained in soy are causally related to protection against
hormone-dependent
cancers. The incidence of
colorectal cancer is at least 30% lower in women than in men in the United States. This suggests that
estrogen and, conceivably, nutritional
phytoestrogens are protective compounds against
colorectal cancer for both sexes. Prevention of colorectal, mammary, and
prostate cancer may also depend on optimal synthesis of the
antimitotic prodifferentiating
vitamin D hormonal metabolite 1,25-(OH)(2)-cholecalciferol (1,25-D3). Cytochrome-P450-hydroxylases responsible for synthesis (
CYP27B1; 25-D3-1 alpha-
hydroxylase) and catabolism (CYP24; 1,25-D3-24-
hydroxylase) of 1,25-D3 are not only present in the kidney but are also expressed in human colonocytes, prostate cells, and mammary cells. In addition, levels of
CYP27B1,
vitamin D receptor, and
estrogen receptor-beta (the high-affinity receptor for
phytoestrogens) are enhanced early during human
colorectal cancer, which suggests an interactive physiological defense against
tumor progression. We demonstrate in human mammary and prostate cells concentration-dependent regulation of
CYP27B1 and of CYP24 by
genistein at 0.05-50 micromol/L. The high concentration of 50 micromol/L is very effective in eliminating CYP24 expression in
prostate cancer cells. This high concentration can be achieved in vivo in the prostate by an as-yet-unknown concentrative mechanism. Soy feeding, or more effectively
genistein feeding, elevates
CYP27B1 and reduces CYP24 expression in the mouse colon. In mice fed low nutritional
calcium, CYP24 rises in parallel to enhanced colonic proliferation, and
genistein counteracts both. We suggest that nutritional soy or
genistein can optimize extrarenal 1,25-D3 synthesis, which could result in growth control and, conceivably, in inhibition of
tumor progression.