Current Knowledge of Vitamin D Metabolism and...
Transcript of Current Knowledge of Vitamin D Metabolism and...
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Current Knowledge of Vitamin D
Metabolism and Function
Glenville Jones, Ph.DCraine Professor & Head, Department of Biochemistry,
Professor, Department of Medicine
Queen's University, Kingston, ON, Canada
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RECENT ADVANCES IN VITAMIN D RESEARCH
• EPIDEMIOLOGICAL STUDIES OF VITAMIN D DEFICIENCY
- SUGGEST ASSOCIATION TO MANY DISEASE STATES
• VDR GENE EXPRESSION STUDIES
- SUGGEST # OF VIT D-DEPENDENT GENES = 300-800
• CLONING OF THE 1α-HYDROXYLASE (CYP27B1)
- WIDESPREAD DISTRIBUTION NOT JUST KIDNEY
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Vitamin D Metabolism & Function
• Review current knowledge of Vitamin D Metabolism
- New information about the cytochrome P450s involved
- Concept of extra-renal 1α-hydroxylase
• Review the classical and non-classical roles of Vitamin D
- Importance of calcitriol in VDR-mediated gene expression
• Implications of vitamin D renaissance for physicians
- Serum 25-OH-D assay as a Biomarker for vitamin D status
- Vitamin D Deficiency may underlie several major diseases
- Vitamin D Supplementation
Objectives:
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CH2
HO
H
H
H
HOH
CH3
CH3
CH3
CH3
CH2
HO
CYP27A1
CYP2R1
Liver
CYP27B1
Kidney
Metabolism of Vitamin D3
Vitamin D3 25-OH-D3
OH
H
H OH
CH3
CH3
CH2
HO
1α,25-(OH)2D3
Calcitriol
Similar pathway exists for vitamin D2
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CH2
HO
H
H
H
HOH
CH3
CH3
CH3
CH3
CH2
HO
CYP27A1
CYP2R1
CYP3A4
Metabolism of Vitamin D3
Vitamin D3 25-OH-D3
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Suda et al. (1977) Vitamin D: Biochemical, Chemical and Clinical
Aspects Related to Calcium Metabolism. 201-213
Perfused Liver reveals two 25-Hydroxylases
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CYP2R1
• LIVER MICROSOMAL VITAMIN D 25-HYDROXYLASE
• SUBSTRATES INCLUDE VITAMINS D3 & D2
& ANTICANCER PRODRUGS (eg 1α-OH-D2)
• MUTATION IN hCYP2R1 AT L99P CAUSES RICKETS
• WORKS AT NANOMOLAR SUBSTRATE & PROBABLY THE
PHYSIOLOGICALLY RELEVANT VIT.D-25-HYDROXYLASE
• SGC (TORONTO) CRYSTALLISED A FUNCTIONAL
HUMAN CYP2R1 WITH VITAMIN D3 IN ACTIVE SITE
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25-Hydroxylation of 1a-OH-D2 by Mouse cyp2R1
1a-OH-D2
1a,25-(OH)2D2
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1α-OH-D2 in CYP2R1
1α,25-(OH)2D2
From : Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park H-W (2008)
Structural Analysis of CYP2R1 in complex with vitamin D3. J Mol Biol 380: 95-106
11α-OH-D2
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Suda et al. (1977) Vitamin D: Biochemical, Chemical and Clinical
Aspects Related to Calcium Metabolism. 201-213
Perfused Liver reveals two 25-Hydroxylases
CYP2R1CYP27A1
CYP3A4
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CH2
HO
H
H
H
HOH
CH3
CH3
CH3
CH3
CH2
HO
CYP27A1
CYP2R1
Liver
CYP27B1
Kidney
Metabolism of Vitamin D3
Vitamin D3 25-OH-D3
OH
H
H OH
CH3
CH3
CH2
HO
1α,25-(OH)2D3
Calcitriol
Similar pathway exists for vitamin D2
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CYP27B1
• KIDNEY MITOCHONDRIAL 1α-HYDROXYLASE
• SUBSTRATES INCLUDE 25-OH-D3 & 25-OH-D2
• MUTATIONS IN hCYP27B1 CAUSE VDDR-RICKETS TYPE 1
• PROBES & ANTIBODIES REVEAL PRESENCE OF CYP27B1
IN EXTRA-RENAL TISSUES eg SKIN, MONOCYTE
• REGULATION DIFFERENT IN DIFFERENT TISSUES:
A) KIDNEY CYP27B1–PTH & FGF-23; Ca & PO4
B) EXTRA-RENAL CYP27B1 -- CYTOKINES
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Janssens W et al (2009) Am J Respir Crit Care Med 179:630-6.
?
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CYP27B1
• KIDNEY MITOCHONDRIAL 1α-HYDROXYLASE
• SUBSTRATES INCLUDE 25-OH-D3 & 25-OH-D2
• MUTATIONS IN hCYP27B1 CAUSE VDDR-RICKETS TYPE 1
• PROBES & ANTIBODIES REVEAL PRESENCE OF CYP27B1
IN EXTRA-RENAL TISSUES eg SKIN, MONOCYTE
• REGULATION DIFFERENT IN DIFFERENT TISSUES:
A) KIDNEY CYP27B1–PTH & FGF-23; Ca & PO4
B) EXTRA-RENAL CYP27B1 -- CYTOKINES
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Thyroid
Plasma Calcium Homeostasis
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Roles of FGF23
1) Increase PO4 excretion
2) Decrease CYP27B1
3) Increase CYP24A1 &
NET INCREASE IN D CATABOLISM
CENTRAL ROLE OF FGF23 IN PHOSPHATE & VITAMIN D HOMEOSTASIS
FGF23
24,25-(OH)2D3
+CYP24A1
HAUSSLER , M
U. ARIZONA, 2009
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CYP24A1
• MITOCHONDRIAL 25-OH-D 24-HYDROXYLASE
IN KIDNEY AND ALL TARGET CELLS
• SUBSTRATES INCLUDE 25-OH-D3 & 1α,25-(OH)2D3
& CYP24 IS A MULTICATALYTIC ENZYME
• INDUCED BY 1α,25-(OH)2D3 & FGF-23 IN TARGET CELLS
• CYP24A1 KNOCKOUT MOUSE SHOWS 50% LETHALITY
• MAJOR ROLE IS CATABOLIC AND EXISTS TO ATTENUATE
ACTION OF CALCITRIOL INSIDE TARGET CELLS
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H
HOH
CH3
CH3
CH2
HO OH
H
H OH
CH3
CH3
CH2
HO
OH
H
H OHOH
CH3
CH3
CH2
HO
OH
OH
H
HOH
CH3
CH3
CH2
HO
OH
H
H OH
CH3
CH3
CH2
HO
O
O
OH
H
H
COOHCH3
CH3
CH2
HO
25-OH-D3 1a,25-(OH)2D3
1a,24,25-(OH)3D3
1a,23,25-(OH)3D3 1a,25-(OH)2D3-26,23-
lactone
Calcitroic Acid
CYP27B1
CYP24
CYP24
Kidney
CH2
HO
H
H
CH3
CH3
Vitamin D3
OH
H
HOH
CH3
CH3
C 2
HO
H
24,25-(OH)2D3
CYP24
CYP27A1
CYP2J3
CYP2R1
CYP3A4
Liver
Metabolism of Vitamin D
Prosser and Jones (2004) Trends in Biochemical Sciences 29:664-73.
BILE
?
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24-hydroxylaseCYP24
+
Calcitroic Acid1a,25-(OH)2D3
Transcriptional up-regulation
CYP24 IS INDUCED BY ITS SUBSTRATE
CYP24
mRNA
β-ACTIN mRNA
Kidney Liver
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CYP24
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 960
20000
40000
60000
80000
100000CYP24-XO-Blood
Wild type
Time (hours)
[3H
] a
s 1a
,25
-(O
H) 2
D3 (
CP
M)
[3H]1a,25-(OH)2D3 in Blood of
Wild type and Cyp24-XO Mice
Masuda et al Endocrinology, 2005
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Blood
Vessel Vitamin D Target Cell
RXR/VDR
RNA Polymerase
Nucleus
VDRE
CYP24
VDR
Vitamin D-dependent gene1a,25-(OH)2D3
DBP
Calcitroic
Acid
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mRNAcytokines
calbindins
25-OH-D3
1a,25-(OH)2D3
Vitamin D3
CYP27A1
Nucleus
Nucleus
megalin/
cubulin
DBP
Megalin/cubulin
kidney
liver
Calcitroic acid
RXR/VDR
VDRE
extra-renal 1a-hydroxylating
target cells
p21
mRNA calbindinsVDRE
p21
osteopontin
normal target cells
RXR/VDR
vitamin D-dependent genes
vitamin D-dependent genes
Vitamin D –Endocrine & Intracrine System
Jones G (2008) Pharmacokinetics of
Vitamin D Toxicity.
Amer J Clin Nutr 88: 582S-586S.
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Vitamin D Metabolism & Function
• Review current knowledge of Vitamin D Metabolism
- New information about the cytochrome P450s involved
- Concept of extra-renal 1α-hydroxylase
• Review the classical and non-classical roles of Vitamin D
- Importance of calcitriol in VDR-mediated gene expression
• Implications of vitamin D renaissance for physicians
- Serum 25-OH-D assay as a Biomarker for vitamin D status
- Vitamin D Deficiency may underlie several major diseases
- Vitamin D Supplementation
Objectives:
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Mechanism of Action of Vitamin D
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Holick M (2006) Mayo Clin Proc 81:353-73.
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Swami et al., (2003) Breast Cancer Res. Treat. 80:49-62.
MCF-7ERa(+)
MB231ERa(-)
2000 Gene Probes
BRCA2
RAB5A
TGFb2
Rb2
Thioredoxin Red.
Integrin aV
VDRCYP24
49
19
1619 Cell Cycle/Apoptosis
6 Cell Adhesion
7 Growth/Immune Mod.
4 Metalloproteinases
3 DNA Repair
2 Steroid Receptors
2 Oncogenes
8 Others
2 Cell Adhesion
5 Cell Cycle/Apoptosis
2 Growth/Immune Mod.
1 Steroid Receptors
1 Oncogene
3 Trans Factors/Kinases
3 Cell Adhesion
2 Growth Factors
1 Kinase
4 Other
3 Cell Adhesion2 Cell Cycle/Apoptosis
5 Growth/Immune Mod.
2 Steroid Receptors3 Kinases
4 Other
14
Microarray Analysis of Calcitriol Treatment
Breast Cancer Cells
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Calcitriol blocks prostaglandin pathways
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Relative risk of Colon Cancer vs Serum 25-OH-D
KDOQI
>30 ng/mL
50% Risk
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1180 WOMEN
FOLLOWED 5 YR
Ca = 1400 mg/d
VITAMIN D = 1100 IU/d
BLOOD 25-OH-D level
Ca+D = 72 96 nmol/L
Ca ONLY = 71 nmol/L
PLACEBO = 71 nmol/L
Am J Clin Nutr 2007; 85:1586-91
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genetic predispostion
Mø
Tc
Fas
MHC-I
b CD28/CTLA-4
CD4TCR
Th1CD40L
TNF-a
IL-1
IL-12APC
(DC) MHC-II
CD80/86
CD40
environment
IL-4
Th1 Th1
IL-10
Th2
IL-2
IFN-g
C. Gysemans
Tc
FasLTCR
CD8Mø
IL-1 TNF-a IFN-gFree radical
(O2-, NO)
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IL-10TGF-b
IL-4IL-5
IL-13
25(OH)D3
Mon/Mf
1αOHase
CD4+T
TCR
CD40
CD40L CD28
DC
MHC II
Ag
IL-12IL-6
TNF-αIL-23
IL-10CCL22
CD80/86
1αOHase
ChemotaxisPhagocytosisCathelicidin
Defensin beta4Reactive oxigen species
25(OH)D3
Tc
IL-1IL-6
TNF-a
target tissue
N°
IL-2
IFN-g
Th17 Th17IL-17
Th1Th1
Th1
Treg Treg
Th2Th2
Th2
Mf
Antimicrobial response
1αOHase
1,25(OH)2D3
CHANTAL MATHIEU, U OF LEUVEN, 2009
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HOLICK –Vitamin D Deficiency-NEJM 357:266-281 (July 19 2007)
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Evidence of a role for 1,25-(OH)2D in Skin
OH
H
H
OH
CH2
HO
CH3
CH3
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1,25-(OH)2D & Renin-Angiotensin System
1,25(OH)2D functions directly and negatively as a novel endocrine
regulator of the renin-angiotensin system in vivo and in vitro
1,25(OH)2D markedly suppresses renin transcription by VDR-mediated
mechanism in cell cultures and animal models
VDR-Knockout animal studies demonstrate the importance of
maintaining normal serum levels of 1,25(OH)2D for proper
homeostasis of calcium, electrolytes, volume, and blood pressure
Li, Yan Chun, Kong, J, The Journal of Clinical Investigation, 2002, Vol. 110, No. 2
VDR
VDR
VDR
-/--/-
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LOWEST 25-OH-DLOWEST 25-OH-D
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10
1,25-(OH)2D & Muscle Differentiation
Counts
Counts
100
100
8 12 14 16 18 20 22
8 10 12 14 16 18 20 220
0
16.5+/-4.4mm
13.8+/-6.2mm
Mean +/- SD
Mean +/- SD
VDR -/-
VDR +/+
VDR -/-
VDR +/+
Myf5 E2A Myogenin MyoD MRF4
Muscle Fiber
Diameter
Protein
Expression
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Vitamin D Metabolism & Function
• Review current knowledge of Vitamin D Metabolism
- New information about the cytochrome P450s involved
- Concept of extra-renal 1α-hydroxylase
• Review the classical and non-classical roles of Vitamin D
- Importance of calcitriol in VDR-mediated gene expression
• Implications of vitamin D renaissance for physicians
- Serum 25-OH-D assay as a Biomarker for vitamin D status
- Vitamin D Deficiency may underlie several major diseases
- Vitamin D Supplementation
Objectives:
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Prevention and treatment of vitamin D insufficiency
and vitamin D deficiency in CKD patients.
.
5 40 100
Deficiency
Insufficiency SufficiencyToxicity
K/DOQI
ng/mL30Adapted from
Hollis Plasma 25-OH-D
Vitamin D intoxication at
25-OH-D >250 ng/mL
SUGGESTED THRESHOLD = 30 ng/mL or 75 nmol/L
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(Jan-Mar)
Deficiency Insufficiency Sufficiency
at Latitude 59º N
(Sep)
17.6 ng/mL 23.6 ng/mL
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CORRECTION OF 25-OH-D INSUFFICIENCY
• INCREASED UV EXPOSURE
- OPPOSED BY DERMATOLOGISTS
• FOOD FORTIFICATION
- MOST FOODS POOR IN VITAMIN D (except SALMON)
- FORTIFICATION VARIES WITH STATE--- Dairy Products
- MILK INTOLERANCE & DOSAGE ISSUES
• ORAL VITAMIN D SUPPLEMENTS
- PRESCRIPTION-VIT. D2 in US (Drisdol)- 50,000 IU/dose
- OTC VITAMIN PILLS-CURRENT DRI- 400-800 IU/day
- OTC “DIETARY D3 SUPPLEMENTS” IN USE- 1000-2000 IU
- NATIONAL ACADEMY OF SCIENCE- NEW DRI-FALL 2010
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TAVERA-MENDOZA & WHITE, Sci Am pp 62-72 (Nov 2007)
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Sources of Vitamin D
Sun (April to October) Diet (Dairy &Fish)
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Summary
• The Vitamin D Metabolic Machinery is series of CYPs operating in a
well-integrated Endocrine-Intracrine system
• 1α,25-(OH)2D has many varied classical and non-classical roles
around the body
• Emergence of extra-renal 1α-hydroxylase emphasizes the value of
serum 25-OH-D assay as a tool to monitor vitamin D status
• Much interest in determining the underlying importance of vitamin D
deficiency/insufficiency in various common diseases
• Vitamin D Supplementation should be considered
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Reviews at <[email protected]>• Jones G, Strugnell S and DeLuca HF (1998)
Current understanding of the molecular actions of vitamin D.
Physiological Reviews 78:1193-1231.
• Prosser DE & Jones G (2004)
Enzymes involved in the activation and inactivation of vitamin D.
Trends in Biochemical Sciences 29:664-73.
• Masuda S & Jones G (2006) The promise of vitamin D analogs in thetreatment of hyperproliferative conditions.
Molecular Cancer Therapeutics 5:797-808.
• Jones G (2007) Expanding role for vitamin D in chronic kidney disease.Seminars in Dialysis 20:316-324.
• Jones G, Horst RL, Carter G, Makin HLJ (2007).
Contemporary Diagnosis and Treatment of Vitamin D-related Disorders.J Bone Mineral Res 22(Suppl. 2):V11-V15.
• Jones G (2008) Pharmacokinetics of Vitamin D Toxicity.
Amer J Clin Nutr 88 (Suppl.): 582S-586S.