Trevor Marshall lecturing on Vitamin D

[Guest guest]

Listmates,

I've put below two links on youtube to a lecture by the Dr. (Ph.D.)

Marshall who developed the Marshall Protocol.

The part that I thought was the most relevant to issues we are thinking

about regarding vitamin D occurs in the second segment at about the fifth

to the 17th minute.

http://www.youtube.com/watch?v=RpocxjKJxag & feature=related

http://www.youtube.com/watch?v=ZMn-zUTTHgw

I certainly see the relevancy of what he said about calcitriol binding

(with the implication of blocking the action of) both the glucocorticoid

receptor and the receptor for T3.

My daughter got back vitamin D testing today. Cholecalciferol was low at

16.5 (rr 32-100) and calcitriol was high at 56 (rr 15.9-55.6). If the

Marshall model is correct, perhaps her serious adrenal fatigue may stem

from calcitriol binding rather than adequate cortisol binding the

glucocorticoid receptor. Perhaps the reason she has responded so well to

T3 (at first) was that there finally was enough to compete with the

calcitriol,but perhaps when more T3 (from increasing the dose of cytomel)

crowded out the calcitriol from binding the wrong receptor, then more of

the calcitriol was available to block the action of the glucocorticoid

receptor. She was not taking high dose vitamin D at the time of the test,

but she had taken a few days before the test a spread out dose of 1200 iu

in a test to see if it would raise her temperature, which it did, but I

don't think she got any more added D as a supplement until this test was done.

It does occur to me that she may have inherited from me something different

about cortisol or the glucocorticoid receptor because when I was on

prednisone as a student younger than she is, my academics got much better

suddenly, but the effect vanished after I got off the drug. Her academics

have been hit very hard in a negative way by this adrenal fatigue.

I certainly hope we will learn enough about this system to predict who may

be helped and who may be hurt by higher doses of vitamin D and I hope we

learn who will need special attention to these other receptors. What I see

as relevant to further understanding this issue is cholesterol levels, and

any genetics related to the three receptors involved. We are going to get

saliva cortisol testing ASAP.

I welcome other thoughts on this, especially after you have listened to

relevant parts of the lecture, or even more of the lecture, if you like.

I haven't yet found corroboration that calcitriol BLOCKS the action of

these other receptors when and if it binds them. I've put below some

things I did find about possible interactions.

1: Biochim Biophys Acta. 2003 Feb 17;1619(3):243-53.

The expression of CYP2B6, CYP2C9 and CYP3A4 genes: a tangle of networks of

nuclear and steroid receptors.

Pascussi JM, Gerbal-Chaloin S, Drocourt L, Maurel P, Vilarem MJ.

Institut National de la Santé et de la Recherche Médicale U128, IFR 24, Centre

National de la Recherche Scientifique, 1919 route de Mende, 34293 05,

Montpellier, France. pascussi@...

Numerous chemicals increase the metabolic capability of organisms by their

ability to activate genes encoding various xenochemical-metabolizing enzymes,

such as cytochromes P450 (CYPs), transferases and transporters. For example,

natural and synthetic glucocorticoids (agonists and antagonists) as well as

other

clinically important drugs induce the hepatic CYP2B, CYP2C and CYP3A

subfamilies

in man, and these inductions might lead to clinically important drug-drug

interactions. Only recently, the key cellular receptors that mediate such

inductions have been identified. They include nuclear receptors, such as the

constitutive androstane receptor (CAR, NR1I3), the retinoid X receptor (RXR,

NR2B1), the pregnane X receptor (PXR, NR1I2), and the vitamin D receptor (VDR,

NR1I1) and steroid receptors such as the glucocorticoid receptor (GR, NR3C1).

There is a wide promiscuity of these receptors in the induction of CYPs in

response to xenobiotics. Indeed, this adaptive system appears now as a

tangle of

networks, where receptors share partners, ligands, DNA response elements and

target genes. Moreover, they influence mutually their relative expression. This

review is focused on these different pathways controlling human CYP2B6, CYP2C9

and CYP3A4 gene expression, and the cross-talk between these pathways.

Publication Types:

Review

PMID: 12573484 [PubMed - indexed for MEDLINE]

2: Nucleic Acids Res. 1997 Nov 1;25(21):4307-13.

Allosteric interaction of the 1alpha,25-dihydroxyvitamin D3 receptor and the

retinoid X receptor on DNA.

Kahlen JP, Carlberg C.

Clinique de Dermatologie, Hôpital Cantonal Universitaire, CH-1211 Genève 14,

Switzerland and Institut für Physiologische Chemie I,

Heinrich-Heine-Universität

Düsseldorf, D-40001 Düsseldorf, Germany.

Genomic actions of the hormone 1alpha,25-dihydroxy-vitamin D3(VD) are

mediated by

the transcription factor VDR, which is a member of the nuclear receptor

superfamily. VDR acts in most cases as a heterodimeric complex with the

retinoid

X receptor (RXR) from specific DNA sequences in the promoter of VD target genes

called VD response elements (VDREs). This study describes a mutation (K45A) of

the VDR DNA binding domain that enhances the affinity and ligand responsiveness

of VDR-RXR heterodimers on some VDREs. In analogy to a homologous mutation

in the

glucocorticoid receptor (K461A), this lysine residue appears to function as an

allosteric 'lock'. Interestingly, overexpression of RXR was found to reduce the

responsiveness and sensitivity of wild type VDR to VD, but enhance the response

of VDRK45A. Moreover, the transactivation domains of both VDR and RXR were

shown

to be essential for obtaining responsiveness of the heterodimers to VD and

9- cis

retinoic acid (the RXR ligand). This indicates that RXR is an active rather

than

silent partner of the VDR on the VDREs tested. Taken together,

transactivation by

VDR-RXR heterodimers can be triggered individually by all components of the

protein-DNA complex, but full potency appears to be reached through allosteric

interaction.

Publication Types:

Research Support, Non-U.S. Gov't

PMID: 9336462 [PubMed - indexed for MEDLINE]

3: Biochem Biophys Res Commun. 1994 Dec 15;205(2):1179-86.

Steroid hormone modulation of vitamin D receptor levels in human MG-63

osteosarcoma cells.

Mahonen A, Mäenpää PH.

Department of Biochemistry and Biotechnology, University of Kuopio, Finland.

The effects of steroid and thyroid hormones are mediated by intracellular

hormone

receptors. An important mechanism modulating target tissue responsiveness to

hormones is homologous and heterologous regulation of the receptors. We have

characterized the expression of steroid hormone receptors in human MG-63

osteosarcoma cells. The MG-63 cells express receptor mRNAs for glucocorticoids,

estrogen, retinoic acid, and 1,25(OH)2D3. We found that only the vitamin D

receptor (VDR) mRNA concentration was influenced by the hormones. The stability

of the VDR message was identical in control, dexamethasone- and

estradiol-treated

cells. On the other hand, both 1,25(OH)2D3 and retinoic acid separately

stabilized the VDR mRNA levels increasing the apparent half-life by 11 h

and 6 h,

respectively. The VDR protein levels, however, as measured by

immunoprecipitation, increased only after the 1,25(OH)2D3 treatment.

Publication Types:

Comparative Study

Research Support, Non-U.S. Gov't

PMID: 7802648 [PubMed - indexed for MEDLINE]

4: Receptor. 1994 Winter;4(4):229-57.

Autoregulation of corticosteroid receptors. How, when, where, and why?

Schmidt TJ, Meyer AS.

Department of Physiology and Biophysics, University of Iowa, Iowa City 52242.

The corticosteroid receptors, including the glucocorticoid and

mineralocorticoid

receptors (GR and MR, respectively), are subject to ligand-mediated

autoregulation like other members of the steroid receptor gene superfamily.

Since

it is the level of expression of these closely related intracellular receptors

that determines cellular sensitivity to adrenal glucocorticoid and

mineralocorticoid hormones, homologous as well as potential heterologous

regulation of GR and MR levels constitute physiologically important homeostatic

events. Although these autoregulatory responses are often exhibited in the form

of receptor down-regulation (negative autoregulation), hormone-mediated

up-regulation (positive autoregulation) has also been documented. Clearly, the

extent as well as direction of hormone-mediated autoregulation of

corticosteroid

receptors vary considerably between different target tissues and cell types and

may be altered during development or as a consequence of aging or disease

state.

Although historically the homologous as well as heterologous regulation of

GR and

MR were evaluated exclusively at the ligand binding levels, the cloning of the

genes for these corticosteroid receptors has facilitated detailed analysis of

hormonal regulation at the message and protein levels. Data generated in

numerous

laboratories have demonstrated that this regulation may be mediated at one or

more molecular levels, including: the transcriptional level, as evidenced

by the

ability of ligand-receptor complexes to decrease the rate of receptor gene

transcription; the posttranscriptional level, as evidenced by the ability

of some

ligands to alter the stability of their own receptor message; and at the

posttranslational level, as evidenced by the ability of agonists to shorten the

half-life of their own receptor protein. In this review we have focused on

several basic questions (how, when, where, and why?) concerning this hormonal

regulation of corticosteroid receptors. Clearly, many of these key questions

concerning autoregulation of GR and MR levels remain unanswered and further

studies in this area will enhance our understanding of the mechanisms

involved in

these cellular events.

Publication Types:

Research Support, Non-U.S. Gov't

Research Support, U.S. Gov't, P.H.S.

Review

PMID: 7894339 [PubMed - indexed for MEDLINE]

5: Endocrinology. 1989 Mar;124(3):1532-8.

Distinct target cells and effects of 1 alpha,25-dihydroxyvitamin D3 and

glucocorticoids in the rat thymus gland.

Provvedini DM, Sakagami Y, Manolagas SC.

Section of Endocrinology/Metabolism, Veterans Administration Medical Center,

Indianapolis, Indiana 46202.

Thymocytes are known to possess receptors for glucocorticoids (GC) as well

as for

alpha, 25-dihydroxyvitamin D3 [1,25-(OH)2D3]. We have now investigated the

distribution of the receptors for GC and 1,25-(OH)2D3 in rat thymocytes and

compared the effects of the two steroid hormones on short term primary cultures

of these cells. We report that in thymic cells, as in other tissues,

1,25-(OH)2D3

and GC bind specifically to distinct receptor molecules which exhibit

sedimentation coefficients of 3.3S and 3.7S, respectively. Furthermore, the

thymocytes that express the 1,25-(OH)2D3 receptor belong to a different and

distinct subpopulation than the cells that express the glucocorticoid receptor.

Specifically, by separating the thymocytes into two subsets by means of

agglutination with the lectin peanut agglutinin (PNA), we have determined that

the 1,25-(OH)2D3 receptor-positive cells belong to the PNA-negative medullary

mature subset, whereas the GC receptor-positive cells belong to the

PNA-positive

cortical immature subset of thymocytes. Finally, we have compared the

effects of

the two steroid hormones on primary cultures of each of the two subsets as well

as on unseparated thymocytes and found that GC act on PNA-positive cells to

induce cell lysis; this leads to an enrichment in 1,25-(OH)2D3

receptor-positive

thymocytes, as indicated by an apparent increase (6-fold) in the 1,25-(OH)2D3

binding in the cells surviving at the end of the culture. In contrast, we found

that 1,25-(OH)2D3 acts on the PNA-negative cells to decrease the rate of cell

lysis. These data indicates that the target cells for GC and 1,25-(OH)2D3

in the

thymus are distinct and that these two hormones exert a different regulatory

influence on the gland.

Publication Types:

Comparative Study

Research Support, U.S. Gov't, Non-P.H.S.

Research Support, U.S. Gov't, P.H.S.

PMID: 2537186 [PubMed - indexed for MEDLINE]

6: J Endocrinol. 1984 Dec;103(3):295-300.

Mechanism of the regulation of the 1 alpha,25-dihydroxyvitamin D3 receptor

in the

rat jejunum by glucocorticoids.

Chan SD, Chiu DK, Atkins D.

The distribution of 1 alpha,25-dihydroxyvitamin D3 (1,25-(OH)2D3) receptors in

isolated jejunal villous and crypt cells was investigated in normal and

adrenalectomized male rats, and also in animals treated with the synthetic

glucocorticoid, dexamethasone, and/or the glucocorticoid antagonist,

11-deoxy-cortisol. Adrenalectomy caused an increase in 1,25-(OH)2D3 receptors

whilst dexamethasone treatment led to a reduction in receptor number.

11-Deoxy-cortisol was able to reverse the 'down-regulation' effect caused by

glucocorticoids. In all cases, the changes in receptor numbers were more

pronounced in crypt cells. The data suggest that, in the small intestine,

glucocorticoids may control the synthesis of 1,25-(OH)2D3 receptors via the

mediation of a glucocorticoid receptor, and that the adrenal hormones mainly

express their effect in crypt cells. It is proposed that this phenomenon

may, in

part, explain the reduction in calcium absorption which occurs in man after

chronic glucocorticoid treatment.

Publication Types:

In Vitro

PMID: 6094696 [PubMed - indexed for MEDLINE]

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