Lithocholic acid derivatives as safer Vitamin D3 substitutes

http://www.sciencedaily.com/releases/2008/03/080314165355.htm

Bile Acids As Drug Candidates

ScienceDaily (Mar. 19, 2008) ‹ Bile acid derivatives can turn on the
vitamin D receptor (VDR) without causing excess calcium buildup,
researchers report, a finding that could lead to vitamin D therapies for
conditions beyond just bone and skin disorders.

While calcium balance may be the most well-known role of vitamin D, this
molecule --through VDR binding-- regulates many functions including
immunity and cell growth and thus has diverse therapeutic potential.

However, while vitamin D-based drugs are effective against some cancers
and microbial infections, the risk of excess blood calcium has limited
their clinical use.
Bile acids, compounds secreted from the liver that aid in digestion, can
also bind to the VDR, though not as strongly.

However, Makoto Makishima and colleagues found that derivates of the
bile acid LCA (lithocolic acid) are very potent VDR activators.
Interestingly, though, these acids did not induce the expression of
calcium channels in various cell types.

The researchers then compared the effects of orally-fed vitamin D or LCA
derivatives on mice; they found that LCA could promote VDR activation in
mice without causing calcium buildup and weight loss that was observed
in vitamin D animals. This study suggests bile acid derivates might have
solid clinical potential.

This research was recently published in The Journal Of Lipid Research.
Adapted from materials provided by American Society for Biochemistry and
Molecular Biology, via EurekAlert!, a service of AAAS.


J Lipid Res. 2008 Apr;49(4):763-72. Epub 2008 Jan 7.
 
Lithocholic acid derivatives act as selective vitamin D receptor
modulators without inducing hypercalcemia.

Ishizawa M, Matsunawa M, Adachi R, Uno S, Ikeda K, Masuno H, Shimizu M,
Iwasaki K, Yamada S, Makishima M.

Division of Biochemistry, Department of Biomedical Sciences, Nihon
University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.

1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], a vitamin D receptor
(VDR) ligand, regulates calcium homeostasis and also exhibits
noncalcemic actions on immunity and cell differentiation. In addition to
disorders of bone and calcium metabolism, VDR ligands are potential
therapeutic agents in the treatment of immune disorders, microbial
infections, and malignancies. Hypercalcemia, the major adverse effect of
vitamin D(3) derivatives, limits their clinical application. The
secondary bile acid lithocholic acid (LCA) is an additional
physiological ligand for VDR, and its synthetic derivative, LCA acetate,
is a potent VDR agonist. In this study, we found that an additional
derivative, LCA propionate, is a more selective VDR activator than LCA
acetate. LCA acetate and LCA propionate induced the expression of the
calcium channel transient receptor potential vanilloid type 6 (TRPV6) as
effectively as that of 1alpha,25-dihydroxyvitamin D(3) 24-hydroxylase
(CYP24A1), whereas 1,25(OH)(2)D(3) was more effective on TRPV6 than on
CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate
and LCA propionate effectively induced tissue VDR activation without
causing hypercalcemia. These bile acid derivatives have the ability to
function as selective VDR modulators.

PMID: 18180267

Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10006-9. Epub 2007 May
29. Related Articles, CoreNucleotide, CoreNucleotide (RefSeq),
Nucleotide (RefSeq), Protein (RefSeq), Cited Articles, Nucleotide,
Protein, Free in PMC
  
Lithocholic acid can carry out in vivo functions of vitamin D.

Nehring JA, Zierold C, DeLuca HF.
Department of Biochemistry, University of Wisconsin, 433 Babcock Drive,
Madison, WI 53706, USA.

The physiological ligand for the vitamin D receptor (VDR) is
1,25-dihydroxyvitamin D(3). Lithocholic acid (LCA), a bile acid
implicated in the progression of colon cancer, was recently shown to
bind to VDR with low affinity and increase expression of the xenobiotic
enzymes of the CYP3A family. Thus, LCA can induce its own catabolism
through the VDR. We have now found that LCA can substitute for vitamin D
in the elevation of serum calcium in vitamin D-deficient rats. Further,
LCA in the diet will also replace vitamin D in the mobilization of
calcium from bone. Further, LCA induces CYP24-hydroxylase mRNA gene
expression in the kidney of vitamin D-deficient rats. It is clear,
therefore, that LCA can be absorbed into the circulation to bind to the
VDR at extra-intestinal sites. These findings lend support for the idea
that the VDR may have evolved from an original role in detoxification.

Publication Types:
* Comparative Study
* Research Support, Non-U.S. Gov't


PMID: 17535892

Best Pract Res Clin Endocrinol Metab. 2006 Dec;20(4):627-45. Related
Articles, Cited in PMC, LinkOut
 
Vitamin D resistance.

Bouillon R, Verstuyf A, Mathieu C, Van Cromphaut S, Masuyama R, Dehaes
P, Carmeliet G.
Laboratory for Experimental Medicine and Endocrinology, Campus
Gasthuisberg, Onderwijs & Navorsing 1, Herestraat 49, bus 902, B-3000
Leuven, Belgium.

Vitamin D is a secosteroid of nutritional origin but can also be
generated in the skin by ultraviolet light. After two hydroxylations
1,25-(OH)2 vitamin D avidly binds and activates the vitamin D receptor
(VDR), a nuclear transcription factor, hereby regulating a large number
of genes. The generation of VDR deficient mice has expanded the
knowledge on vitamin D from a calcium-regulating hormone to a humoral
factor with extensive actions. The effects of the vitamin D system on
calcium and bone homeostasis are largely mediated by promoting active
intestinal calcium transport via the induction of the epithelial calcium
channel TRPV6. Although VDR is redundant in bone, it may regulate the
differentiation and function of several bone cells. In skin, VDR
expression in keratinocytes is essential in a ligand-independent manner
for the maintenance of the normal hair cycle. Therefore, VDR but not
vitamin D deficiency results in alopecia. Moreover, 1,25-(OH)2 vitamin D
impairs the proliferation not only of keratinocytes but also of many
cell types by regulating the expression of cell cycle genes, leading to
a G1 cell cycle arrest. In addition, VDR inactivation in mice results in
high renin hypertension, cardiac hypertrophy and thrombogenesis.
Finally, a dual effect of vitamin D was observed in the immune system
where it stimulates the innate immune system while tapering down
excessive activation of the acquired immune system. Taken together, the
vitamin D endocrine system not only regulates calcium homeostasis but
affects several systems mainly by altering gene expression but also by
ligand-independent actions.

Publication Types:
* Review

PMID: 17161336