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478 Fat-soluble Vitamins and Non-nutrients

White JA, Ramshaw H, Taimi M, Stangle W, Zhang A, Everingham S, Creighton S,

Tam SP, Jones G, Petkovich M. Identification of the human cytochrome P450,
P450RAI-2, which is predominantly expressed in the adult cerebellum and is respon-
sible for all-trans-retinoic acid metabolism. Proc Natl Acad Sci USA 2000;97:
Yeum KJ, dos Anjos Ferreira AL, Smith D, Krinsky NI, Russell RM. The effect of alpha-
tocopherol on the oxidative cleavage of beta-carotene. Free Rad BioI Med 2000;
29: 105-14
Yeum KJ, Russell RM. Carotenoid bioavailability and bioconversion. Annu Rel' Nlllr
Yeum KJ, Lee-Kim YC, Yoon S, Lee KY, Park IS, Lee KS, Kim BS, Tang G, Russell RM,
Krinsky NI. Similar metabolites formed from beta-carotene by human gastric
mucosal homogenates, lipoxygenase, or linoleic acid hydroperoxide. Arch Biochem
Biophys 1995;321:167-74
Zhuang R, Lin M, Napoli JL. cis-Retinol/androgen dehydrogenase, isozyme 3 (CRAD3):
a short-chain dehydrogenase active in a reconstituted path of 9-cis-retinoic acid
biosynthesis in intact cells. Biochem 2002;41 :3477-83

Vitamin D
The most common form of vitamin D in foods is vitamin D3 (9, I 0-seco(5Z, 7E)-cholesta-
5,7,10( 19)-trien-3-ol, cholecalciferol, colecalciferol, oleovitamin D 3 ; molecular
weight 384). The less common form vitamin D2 (ergocalciferol) is slightly less effective.

02 vitamin O2
03 vitamin 0 3
OBP vitamin O-binding protein
25-0 25-hydroxyvitamin 0
1,25-0 1a,25-dihydroxy-vitamin 0
24,25-0 24R,25-dihydroxy-vitamin 0
PTH parathyroid hormone
UV-B ultraviolet Blight (290-315 nm)

Nutritional summary
Function: Promotes intestinal absorption of calcium and its retention in the body.
Through its role in gene regulation the active form, la,25-dihydroxy-vitamin D (1,25-
D), it influences growth of bone and connective tissues and may protect against some
forms of cancer.
Requirements: Adults should get at least 5 I-lg/day, three times as much with
advanced age.
Vitamin D 479

Vitamin D3

Figure 9.12 Dietary compounds with vitamin D activity

Sources: Fatty fish and fortified milk are good dietary sources; eggs, fortified cereals.
and fortified margarines contribute smaller amounts. A young person gets a full day's
supplies from 10-15 minutes of face and arm exposure to summer sun (ultraviolet B,
UV-B, 290-315 nm), an older person needs several times longer exposure.
Deficiency: A severe lack during childhood causes rickets, characterized by bone
deformities in lower limbs (bowlegs) and chest. Deficiency at a later age causes loss
of bone minerals (osteoporosis). in the most severe cases of both minerals and connective
tissue (osteomalacia). Tetany and severe bone pain are characteristic signs. People with
suboptimal vitamin D status tend to have elevated parathyroid hormone levels and
absorb dietary calcium less well. Indicative symptoms for mild vitamin D deficiency
include fatigue, muscle ache, and diffuse bone pain (Nykjaer et al., 2001).
Excessive intake: Prolonged consumption of several hundred micrograms per day may
cause hypercalcemia and soft tissue calcification. Continued exposure to doses of
thousands of micrograms daily may cause coma and death in extreme cases.

Endogenous sources
Exposure of skin to ultraviolet light with wavelengths between 290 and 315 nm (UV-B)
converts some of the cholesterol precursor 7-dehydrocholesterol to previtamin D3,
which rearranges spontaneously to vitamin D3 (Holick et al . 1989). Suberythemal (a
dose that does not cause sunburn) irradiation of skin with UV-B (0.5 J/cm 2) was found
to convert about one-third of endogenous 7-dehydrocholesterol (2.3IJ.g/cm2) into pre-
vitamin D3, and another third into the precursor lumisterol and the inactive metabolite
tachysterol (Obi-Tabot et al., 2000). UV-B inactivates some of the newly generated
vitamin D and its unstable precursors. Vitamin D synthesis rapidly becomes maximal
upon continued exposure. because light-induced production and destruction of vitamin D
reach an equilibrium. It has been estimated that exposure of the entire body to sum-
mer sun for less than 20 minutes is sufficient to generate vitamin D in skin equivalent to
an oral dose of 250 IJ.g or more (Vieth, 1999).
Skin pigmentation decreases the effective light dose and greatly decreases vitamin D
production with less than maximal sun exposure (Kreiter et al., 2000).
480 Fat-soluble Vitamins and Non-nutrients

The diminished vitamin D production in older people (75% decline by age 70) has
been attributed in part to a lower concentration of un esterified 7-dehydrocholesterol in
skin (Holick, 1999).

Dietary sources
Most natural vitamin D is consumed in the form of vitamin D3 (D3, cholecalciferol). The
content of foods is expressed in jJ.g or International Units (I jJ.g = 40 IU). The only


Previtamin D3

nonenzymic (inactive)


Vitamin D3
H,C (inactive)


Suprasterol II


Figure 9.13 Lighrinduced synrhesis of vir am in D J

Vitamin 0 481

natural foods that contain the structurally related vitamin D2 (D2, ergocalciferol) are
mushrooms. Ocean fish is the main dietary source of D3. Particularly rich sources are
the fatty types of fish, such as salmon (0.1-0.3 j.Lg/g), sardines (0.4 j.Lg/g), and mack-
erel (0.1 j.Lg/g). Lean ocean fish, such as cod (0.01 j.Lglg), and freshwater fish, contain
only little vitamin D.
Most milk in the US is fortified at a level of 5 j.Lg/l. Considerable variation of actual
milk vitamin D content have been observed in the past, however (Holick el al., 1992).
Other dairy products, such as yoghurt or cheese, are not usually fortified. D2, which
is the compound originally used for fortification, has been replaccd with D3 in the US
and many other countries. Vitamin D2 can be produced relatively simply by UV light
irradiation of lanosterol. D2 is biologically less active than D3 (Trang el al., 1998).
Typical daily vitamin D intakes in North American women may be as low as 2.5 j.Lg
(Krall el al., 1989), and usually insufficient to prevent suboptimal vitamin D status in
regions with low sunlight exposure (Vieth, Cole et al., 200 I). In Denmark, where milk
does not contain added vitamin D, median daily intakes around 3 j.Lg in men, and
around 2 j.Lg in women were recorded (Osler et al., 1998). Even lower median intakes
(1.2 j.Lgld) were reported for Australians (Pasco el al., 200 I). Older people in particular,
who need much more vitamin D (at least 10 j.Lg for ages 51-70, and IS j.Lg for people
over 70) than younger people, commonly do not get enough (Kohlmeier et al., 1997).

Digestion and absorption

Vitamin D is highly fat-soluble and becomes part of mixed micelles (consisting mainly
of bile acids, phospholipids, fatty acids and monoglycerides) during fat digestion.
Nearly all of the ingested vitamin D is absorbed. The vitamin enters the small intestinal

vitamin 0

";'_ _ ~vitamin 0 - - - - . . e

Intestinal Enterocyte Lymph

lumen duct
Brush border Basolateral
membrane membrane

Figure 9.14 Intestinal absorption of vitamin D

482 Fat-soluble Vitamins and Non-nutrients

cell along with fatty acids and other lipids in an incompletely understood process.
Chylomicrons then carry vitamin D into lymph vessels and eventually into blood cir-
culation. Little, if any, vitamin D is released while the chylomicrons circulate and rapidly
lose most of their triglyceride load. The liver takes up about half of the triglyceride-
depleted chylomicrons through a receptor-mediated process that involves apolipoprotein
E and the LDL receptor. Bone marrow and bone take up about 20%, and other extra-
hepatic tissues clear the remainder. Vitamin D reaching the liver can be secreted again
into circulation as a complex with vitamin D-binding protein (DBP, group-specific
component, Gc).

Transport and cellular uptake

Blood circulation: Vitamin D and all its normal metabolites in blood are bound to
DBP. Almost all of the vitamin D in circulation is 25-hydroxy-vitamin D (25-D);
much smaller amounts are 1,25-dihydroxy-vitamin D ( I ,25-D). Typical 25-D concen-
trations in plasma of young adults living under sun-rich conditions are well in excess
of 100 nmolll (Vieth, 1999). Nonetheless, the lower limit of reference ranges is com-
monly set to 50 nmolll or lower. Average 25-D concentrations of people Iiving at lati-
tudes of 50 or higher may be as low as 40 nmolll during the winter months (Trang et al.,
1998). Typical 1,25-D concentrations in vitamin D-replete people tend to be around
100 pmoili. 25-D concentrations are low in vitamin D-deficient people, intermediate
with adequate status, and increase further with excessive dietary intakes (but not with
very intense UV light exposure). 1,25-D concentrations also are low in vitamin D
deficiency, but do not increase further after adequate vitamin D intakes are exceeded.
Thus, 25-D concentration in plasma is a good marker to reflect both inadequate and
excessive vitamin D supplies.
It has been the traditional view that because of their high fat solubility vitamin
metabolites can cross plasma membranes by simple diffusion. A more directed entry
pathway may pertain in some tissues, however, such as endocytotic uptake mediated by
cubilin andlor megalin (LDL-receptor related protein 2, LRP2).
Blood-brain barrier: Transport of vitamin D metabolites from blood into brain is very
limited (Pardridge et al., 1985). The underlying mechanisms are not well understood.
Materna-fetal transfer: 25-D is the main metabolite supplied by the mother to the fetus
through incompletely understood mechanisms (Salle et al., 2000). Fetal concentrations
are lower than on the maternal side. Vitamin D is not only transferred to the fetus, but
also has important functions in the placenta itself. It is no surprise, therefore, that
placenta expresses the vitamin D activating enzyme 25-hydroxy-vitamin D(3 )-1
a-hydroxylase (Zehnder et al., 2001).

Vitamin D is metabolized extensively in liver, intestines, and kidneys. More recent
evidence shows that keratinocytes in skin are fully autonomous in respect to vitamin D
metabolism and are capable of all major activating and inactivating reactions (Schuessler
et al., 200 I ). Similarly, osteoblasts, parathyroid cells. myelocytes and other cell types
Vitamin 0 483

have relevant metabolic activity. Three best-recognized enzyme reactions produce two
biologically active metabolites, la,25-dihydroxy-vitamin 0 and 24R,25-dihydroxy-
vitamin 0 (Norman, 2001).
Microsomal vitamin 0(3) 25-hydroxylase (CYP2025, identical with sterol-27
hydroxylase, CYP27 A) in liver and intestines catalyzes the essential first step in the
bioactivation of the pro hormone vitamin 0 (Theodoropoulos et al., 200 I). This reaction
is so effective upon first pass of newly absorbed vitamin 0 through small intestine and
liver, that blood contains very little unmetabolized vitamin O.
Activation to Ia,25-dihydroxy-vitamin 0 (1,25-0) is completed in proximal tubular
epithelial cells of the kidneys by caIcidiol l-monooxygenase (25-hydroxy-vitamin 0-1 a-
hydroxylase, CYP27Bl, P450CI-a, ECI.I4.13.13), a mitochondrial cytochrome P450



ox,dlZed NADPH
vitamin 0(3) terredox,nJEADPH.ferredOXin
25-hydroxylase reductase (FAD)
(heme) reduced
ferredOXin NADP



25-Hydroxy-Vitamin D3



calcidiol terredoxin
1-monoxygenase "y';;AOPH.ferredoxin
(heme) reduced J\..eductase (FAD)
ferredoXin NAOP



1" .25-Dihydroxy-Vitamin 0 3


ow OH

Figure 9.15 Vitamin D activation depends on renal filtration and reabsorption

484 Fat-soluble Vitamins and Non-nutrients

red.lerredoxin ox. ferredoxin

+02 \ ) + H,o
1fl,25-0ihydroxy- CYP? OH
vitamin 0 3 1fl.23S,25-Trihydroxy-
vitamin 0 3

CH 2 CYP24 + O2 ?
OH- OH + H,o

la.24R,25 XS1;H
Trihydroxy-vitamin D3

CYP24 2

la.25-0ihydroxy- y() -0 + H,o

24-oxo-vitamin 0 3 /J ~OH C-23 oxidation C-24 oxidation

pathway pathway

. ~x8~[Sedoxin
oxidized NADPH

la.23S,25-Trihydroxy- -0
24-oxo-vitamin 0 3 /J ~OH reduced
reductase (FAD)



+ 2
ox. ferredoxin
+ H,o + C4 fragment

COH redJerredoxin ox.ferredoxin
1fl.25-Trihydroxy-24-oxo- +02 \ ) + H,?
vitamin 0 3 CYP?



Figure 9.16 Catabolic pathways for 1ll',24R,2S-trihydroxy-viramin D,

oxidase. Ferredoxin, which provides the reducing equivalents for all cytochrome P450
systems, is regenerated by ferredoxin-NADP reductase (EC 1.18.1 ,2, FAD-containing),
Before this hydroxylation can take place, however, the 25-0 precursor has to reach
the tubular cell. The main, and possibly exclusive route is glomerular filtration of the
25-D/DBP complex and endocytosis mediated jointly by cubilin and megalin (Nykjaer
et aI" 2001). Decreased filtration rate (as with advancing age or in renal failure) or defec-
tive cubilin or megalin diminish the production of 1,25-0. Some 25-0 hydroxylation
also occurs in extrarenal cells including skin and white blood cells (Hewison et al .. 2000;
Schuessler et al . 200 I). The glomerular filtration rate of a healthy man can be expected
to fall from about 140 mllminute at age 20 to about 90 ml/minute by age 70 (Lindeman.
1999). This age-typical decline in renal function raises the threshold plasma 25-0 con-
centration that sustains adequate 1.25-0 production by more than half. A several-fold
Vitamin D 48S

vitamin D3


oxidized NADPH

reduced )(eductase (FAD)
ferredoxin NADP


24A .25-Dihydroxy-
vitamin D3

OH C24 oxidation

"" "" COOH

23-hydroxy- -
tetranor-vitamin D3



Figure 9.17 Catabolism of 2S-hydroxy-vitamin D

increase in dietary intakes or endogenous production is necessary to make up for this dif-
ference (Vieth, 1999). Current recommendations recognize that people over 70 years
of age need three times more vitamin D than young adults (Institute of Medicine, 1997).
Another mitochondrial cytochrome P450 oxidase, 25-hydroxy-vitamin D-24R-
hydroxylase (CYP24) converts 1.25-D into la,24R,25-trihydroxy-vitamin D (24,25-
D). Alternatively, hydroxylation at carbon 23 may occur. Irreversible 3-epoxidation
initiates a distinct metabolic pathway. Hydroxylations of the side chain, possibly with the
involvement ofCYP24 (Inouye and Sakaki, 200 I), generate the water-soluble metabolite
calcitroic acid (la-hydroxy-24,25,26.27-tetranor-23-carboxyl-vitamin D).
The bulk of 25-D is catabolized through the C24 oxidation pathway with 24R.
25-dihydroxy-vitamin D3 as an important intermediate metabolite (Henry. 200 I). which
may have its own specific biological activities.
Numerous additional hydroxylated and otherwise modified metabolites are present
in blood and tissues. While it has been held that calcitroic acid and other metabolites
486 Fat-soluble Vitamins and Non-nutrients

1n.hydroxy-3-epi-vitamin 0 3 , 1n.hydroxy-3-epi-vitamin 0 3 I
20.2S-cyclic ether 24.2S-epoxide


Figure 9.18 Metabolites derived from vitamin Dr 3-epi-intermediates

are inactive, more recent investigations seem to indicate that they retain some typical
vitamin D activity (Harant et al., 2000).

Vitamin D is known to be stored extensively in the liver. These stores sustain normal
vitamin D-dependent functions during the winter at high latitudes even in the absence
of significant dietary intakes. However, quantitative data on amounts stored alterna-
tive storage sites, or the precise mechanisms for deposition and release, are not available.
Smaller amounts of vitamin D are stored in extrahepatic tissues. The cartilage
oligomeric matrix protein may provide a local storage mechanism that supports rapid
delivery to nearby target structures (Guo et al., 1998).

Calcitroic acid the 3- and 24-glucuronides of 24,25-D, and additional vitamin D
metabolites are excreted with bile. Since intestinal absorption of vitamin D is very
efficient, losses of active vitamin D via this route are likely to be minor. Quantitative
information in this regard is limited however_
25-D in plasma is bound to DBP (group-specific component, Gc), a single peptide
chain with molecular weight of 52 000 (Witke et al., 1993). A small percentage of this
complex is filtered in the renal glomeruli. DBP binds with high affinity to cubilin at the
brush border membrane of the proximal renal tubule, as described above. Megalin assists
with the endocytosis and intracellular trafficking of cubilin and all its captured ligands
(which include retinol-binding protein and transferrin among others). Due to the high
efficiency of the process very little of the filtered vitamin D escapes with urine. Calcitroic
acid is a major catabolite of both vitamin D2 and D3 in urine (Zimmerman et al., 200 I).

Feedback inhibition strongly limits 1,25-D production (Norman, 200 I). The main
activator of renal production of 1,25-D is PTH, which increases expression of
I a-hydroxylase (Theodoropoulos et al., 200 I ). Calcitonin, estrogen, prolactin, insulin,
growth hormone, and glucocorticoids also activate this key enzyme.
Vitamin D 487


~~~~~tin ::)
growth hormone
vitamin 0

Figure 9.19 Regulation of 1cr,2Sdihydroxy'vitamin 0 synthesis

Conversely. 1.25-0 decreases PTH secretion both directly by acting on a VORE in the
promoter of the PTH gene and indirectly through its effects on calcium and phosphate
concentrations in blood and extracellular fluid (Sela-Brown el al . 1999). PTH also
promotes the conversion of 25-0 to 24.25-0 (Armbrecht el al . 1998).

Nuclear effects: A complex consisting of 1.25-0. the nuclear vitamin 0 receptor (VOR).
and the retinoid X receptor (RXR) binds to spccific vitamin 0 response elements (VORE)
in the nucleus and modifies the rate of expression of the associated genes. RXR must
contain the vitamin A metabolite 9-cis-retinoic acid in order to form the active receptor
complex. VORE increase the expression of many genes including osteocalcin. osteo-
pontine alkaline phosphatase. calbindin-9K. and calcium-transporting ATPase. Oown-
regulated genes include those for many collagens. and for cell cycle regulators such
as c-myc. c-fos. c-sis. and ubiquitin-conjugating enzyme 2 variant 2 (UBE2V2).
Intestinal calcium absorption: The overall consequence of improved vitamin 0 status in
sma II intestinal celIs is faster calcium influx trom the lumen. more efficient transcellular
calcium transfer. and accelerated calcium pumping towards the bloodstream. These
effects all add up to considerably increased fractional calcium absorption. Phosphate
absorption also increases slightly. Daily oral doses of 1.25-0 between 0.5 and 3 ~g are
sufficient to increase intestinal calcium absorption. The effect of25-0 on intestinal cal-
cium absorption is much smaller. It has been estimated that as much as one eighth of the
vitamin O-related absorption-enhancing action is due to 25-0 (Heaney el al. 1997).
Fractional calcium absorption from small intestine increases much more rapidly
(within seconds. sometimes referred to as transcaltachia) than could be explained by
effects on protein expression. It has been postulated therefore. that these rapid
changes are mediated by an as yet unidentified 1.25-0 receptor at the plasma mem-
brane (Norman. 2001).
Effects on bone: 1.25-0 acts directly on hematopoietic stem cells and induces the gen-
eration of osteoclast cells. These migrate into bone. start breaking down bone matrix
488 Fat-soluble Vitamins and Non-nutrients

and minerals, and release calcium and phosphate. The various effects of I ,25-D on the
osteoblast nucleus have been alluded to above, and are mainly mediated by the vitamin
D-receptor/retinoic X receptor complex. The increased expression of alkaline phos-
phatase, osteoealcin, and osteopontin supports the control of minerals released by osteo-
clast action and orderly redepositing of any excesses.
There is persuasive evidence that 24,25-D is needed for proper bone mineralization
in addition to 1,25-D (Norman, 2001; van Leeuwen et al., 2001). Some of the actions
of 24,25-D may be mediated through a plasma membrane receptor that is different
from the nuclear vitamin D receptor. The significance of 24,25-D remains in dispute,
however, since information on this metabolite is much more limited than on 1,25-D.
Cell differentiation: An important effect of vitamin D is on growth and maturation of
a wide range of cell types. For example, 1,25-D regulates the differentiation of
keratinocytes (Bikle et al., 200 I). I ,25-D also influences quiescence, modulates growth
factors, promotes apoptosis of cancer cells and slows metastasis in model systems.
Suboptimal vitamin D status is likely to increase the risk of cancer of prostate (Polek
and Weigel, 2002), breast (Colston and Hansen, 2002), and other sites. There are
ongoing efforts to develop vitamin D analogs that retain their antiproliferative potency
while minimizing hypercalcemic effects.
Other cellular effects: The plasma-membrane receptor described above (Norman, 200 I )
may mediate rapid effects of I ,25-D on various cells. 1,25-D stimulates, among others,
the rapid calcium influx into osteoblasts and other cells through voltage-gated calcium
channels, the release of calcium from stores in muscle cells, and the activation of
mitogen-activated kinase.

Armbrecht HJ, Hodam TL, Boltz MA, Partridge NC, Brown AJ, Kumar VB. Induction of
the vitamin D 24-hydroxylase (CYP24) by I ,25-dihydroxyvitamin D3 is regulated by
parathyroid hormone in UMR \06 osteoblastic cells. Endocrino/1998; 139:3375-81
Bikle DD, Ng D, Tu CL, Oda Y, Xie Z. Calcium- and vitamin D-regulated keratinocyte dif-
ferentiation. Mol Cell Endocrinol2001; 177: 161-71
Colston KW, Hansen CM. Mechanisms implicated in the growth regulatory effects of
vitamin D in breast cancer. Endocrin Rei Cancer 2002;9:45-59
Guo Y, Bozic D, Malashkevich VN, Kammerer RA, Schulthess T, Engel J. All-trans
retinol, vitamin D and other hydrophobic compounds bind in the axial pore of the
five-stranded coiled-coil domain of cartilage oligomeric matrix protein. EMBO J
1998; 17:5265-72
Harant H, Spinner D, Reddy GS, Lindley IJ. Natural metabolites of lalpha,25-dihydroxy-
vitamin D(3) retain biologic activity mediated through the vitamin D receptor. J Cell
Biochem 2000;78: 112-20
Heaney RP, Barger-Lux MJ, Dowell MS, Chen TC, Holick MF. Calcium absorptive effects
of vitamin D and its major metabolites. J Clin Endocrinol Metah 1997;82:4111-16
Henry HL. The 25(OH)D)/la,25(OHhD r 24R-hydroxylase: a catabolic or biosynthetic
enzyme? SteIVids 200 1;66:391-8
Hewison M, Zehnder D, Bland R, Stewart PM. I alpha-Hydroxylase and the action of vita-
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Metaholism, 4th edn. Lippincott Williams & Wilkins, Philadelphia, 1999. pp.92-8
Holick MF, Matsuoka LY, Wortsman J. Age, vitamin 0, and solar ultraviolet radiation. Lancet
Holick MF. Shao Q, Liu WW, Chen TC. The vitamin 0 content of fortified milk and infant
formula. N Eng/ J Med 1992;326: 1178-81
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Obi-Tabot ET, Tian XQ, Chen TC, Holick ME A human skin equivalent model that mimics
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Vitamin E
Vitamin E (RRR-alpha-tocopherol, 3,4-dihydro-2,5,7 .8-tetramethyl-2-( 4,8, l2-trimethyl-
tridecyl)-2H-I-benzopyran-6-ol, 2.5,7,8-tatramethyl-2-(4'.8', l2'-trimethyltrdecyl) 6-
chromanol. 5.7,8-trimethyltocol; obsolete name antisterility vitamin; molecular
weight 430); there are seven stereoisomers of alpha-tocopherol with lower activity.
The related compounds beta-, gamma-. and delta-tocopherol, tocotrienols. and others
have more limited activity.

vitE vitamin E (all forms)
HDL high-density lipoproteins
LDL low-density lipoproteins
TAP tocopherol-associated protein
TBP tocopherol-binding protein
TIP alpha-tocopherol transfer protein
VLDL very-low-density lipoproteins