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7-Reductase1, ,2
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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7-reductase (EC 1.3.1.21) in
the diet. Cats receiving the inhibitor had a progressive increase in
25-OHD concentration of plasma with time to 91 ± 22 nmol/L
(mean ± SEM), whereas cats not receiving the
inhibitor had plasma 25-OHD concentrations that were not detectable
(P < 0.001). Biopsy samples of skin from cats
receiving the inhibitor had more than five times the concentration of
7-dehydrocholesterol (P < 0.001) than the skin of
control cats. Low concentration of 7-dehydrocholesterol (presumably due
to high activity of the reductase) in the skin of cats is the major
impediment to effective vitamin D synthesis. Analysis of wild caught
potential prey of cats indicated that these animals could supply
adequate vitamin D to meet the requirement of growing kittens.
KEY WORDS: • cholecalciferol • 7-dehydrocholestrol-7-reductase • vitamin D synthesis • Cats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), the extent and time of skin exposure
(Holick 1989
) and skin pigmentation (Clemens et al. 1982
). Gershoff et al. (1957)
reported
vitamin D deficiency in 3- to 6-mo-old kittens given a purified vitamin
D-free diet and showed that clinical signs of deficiency could be
prevented by oral administration of 6.25 µg of cholecalciferol twice
weekly. However, a high incidence of deaths occurred in kittens given
the purified diet supplemented with vitamin D, so this estimate of the
requirement is open to question. As Gershoff suggested a relatively low
requirement for vitamin D in cats, it was subsequently assumed that
"the cat kept in a well-lighted room is almost independent of dietary
sources of this vitamin: (and) probably vitamin D is synthesized in the
cat's skin and ingested while it is grooming its coat" (Scott and Scott 1967
). Rivers et al. (1979)
observed
no signs of vitamin D deficiency in adult cats fed a vitamin D-free
diet for over a year and suggested that the requirement of vitamin D
for adult cats may be very low. In 1986 the National Research Council
on the basis of these two experiments proposed a minimal vitamin D
requirement for growing kittens of 12.5 µg (500 IU)/kg diet dry
matter.
Hazewinkel et al. (1987)
demonstrated that vitamin D
synthesis was defective in dogs that had their backs shaved when
exposed to UV light, and these dogs developed clinical signs of vitamin
D deficiency. Subsequently, How et al. (1994)
reported
that they were unable to demonstrate the presence of pre-vitamin D in
isolated cat skin exposed to UV light.
The objective of this series of experiments was to determine if cats
could effectively synthesize vitamin D in their skin on exposure to UV
light, and if synthesis was not effective, to determine the impediment
to synthesis. Plasma concentration of 25-hydroxyvitamin D (25-OHD) was
used to asses the vitamin D status of kittens. Holick (1990)
recommended that plasma concentration of 25-OHD was the
preferred index of vitamin D status. Plasma 25-OHD is more stable than
that of either vitamin D or calcitriol, as the half life of 25-OHD in
the plasma of humans is about 3 wk. In contrast, the half-life of
vitamin D is about 24 h and calcitriol 4 to 6 h
(Holick 1990
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Specific-pathogen-free cats or kittens from the Feline Nutrition and
Pet Care Center, University of California-Davis, Davis, CA, were used
in all experiments. Kittens with the exception of those exposed to
sunlight were housed in temperature-controlled rooms (20 ±
2°C), and food and water were available at all times unless stated. A
purified diet (Table 1
)was used in all experiments. This diet contained major nutrient and
vitamin concentrations (other than vitamin D) at levels greater than
those recommended by the National Research Council (1986)
. The mineral mixture was one that has been used with
purified diets for > 15 y in our laboratory and has
supported excellent growth rates (exceeding 30 g/d) in male kittens.
Experimental protocols were approved by the University of
California-Davis Animal Use and Care Administrative Advisory Committee
and were carried out in accordance with standards of the Guide
for the Care and Use of Laboratory Animals of the National
Institutes of Health.
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Roof rats (Rattus rattus L.) and mice (Mus musculus) were trapped outside the City of Davis to exclude potential exposure to human or animal foods fortified with vitamin D. The two birds analyzed had flown into plate glass windows and were killed immediately. The laboratory rats had been raised on a complete pelleted diet (Rat Diet # 5012; PMI Feed Inc., St. Louis, MO). Whole bodies (birds without feathers) were ground with dry ice preparatory to analysis for vitamin D.
Analytical Methods.
Analysis for vitamin D.
Diet and food samples were analyzed by a modification of the
high-performance liquid chromatography (HPLC) procedures of
Holick et al. (1992)
. Foods, especially those containing
animal tissue, contain interfering substances that require extensive
clean up preparatory to chromatography. Either 14C- or
3H-labeled cholecalciferol tracer that had been purified by
HPLC chromatography was used to determine recovery rates.
Sample preparation for HPLC. A sample of food or diet (~10 g of dry matter) was weighed and combined with the tracer (~500 Bq), 3 g of ascorbic acid, 90 mL of ethanol and 10 mL of 800 g/L KOH in water in a round-bottom flask with a stirring bar and refluxed over a hot plate-stirrer for 1 h. After cooling, the digest was filtered in a 11-cm Buchner funnel with a coarse (Whatman No. 1) filter paper under partial vacuum. The residue on the filter paper was washed with 20 mL of ethanol then 50 mL of hexane, the combined filtrate was transferred to a 500-mL separating funnel, and 80 mL of water was added. After tumbling (to prevent formation of an emulsion) the funnel about 100 times, the organic layer was allowed to separate and drained into a clean separating funnel. The filtrate was extracted two more times with 50 mL aliquots of hexane, the three extracts were pooled and 0.1 mL of butylated hydroxy toluene solution (10 g/L hexane) was added. The combined hexane extracts were washed three or more times with 100 mL of water or until the water was neutral to phenolphthalein. The hexane extract was then dried over 10 g of anhydrous sodium sulfate, transferred to a 250-mL round-bottom flask and reduced to about 5 mL in a rotary evaporator. The solution was then transferred along with washings to a 15-mL Teflon-lined screw-capped test tube and dried under nitrogen. The residue was taken up in 1 mL of 0.4% isopropanol in hexane and placed on a prepared silica Sep-Pak Vac RC 500-mg cartridge (Waters part # 51900). The column was washed with 10 mL of 0.4% isopropanol in hexane which was discarded to waste and then eluted with a further 10 mL of 0.4% isopropanol in hexane, which was collected and dried under nitrogen. The dry residue was then dissolved in 1 mL of methanol and transferred to a Bond Elut LRC 500-mg C-18 cartridge (Varian Associates Inc., Harbor City, CA) that had been previously prepared by sequential washings of 5 mL of hexane, 5 mL of methanol and 5 mL of water. The C-18 column was sequentially eluted with 5 mL of water, 15 mL of a mixture of methanol, tetrahydrofuran and water (1:1:2 parts), 10 mL of a mixture of 70% methanol 30% water and 5 mL of acetonitrile (all to waste). The column was then eluted with 5 mL of methanol, which was collected and dried under nitrogen.
HPLC separation. Two HPLC separations were used, a straight-phase separation to isolate ergocalciferol and cholecalciferol in a single peak, followed by a reversed-phase separation to isolate ergocalciferol from cholecalciferol. The straight-phase separation used a silica column (Econosil 5 µ 250 x 4.6 mm; Alltech, San Jose, CA) with isocratic 0.6% isopropanol in hexane mobile phase at a flow rate of 2 mL/min and the UV detector set to 265 nm and AUFS of 0.02. The reversed-phase separation used a C-18 column (Vydac C-18, 5 µ 150 x 4.6 mm; The Separations Group, Hesperia, CA) with an isocratic mobile phase of methanol/acetonitrile (25:75) at a flow rate of 1 mL/min and the UV detector set at 265 nm. Dried samples were taken up in the mobile phase before chromatography. Recoveries of the isotope were generally >0.6. Corrected recoveries of diet samples containing 25 µg of cholecalciferol/kg were 1.03 and 1.05 times the theoretical values.
Measurement of 7-dehydrocholesterol (7-DHC) in skin.
Samples of skin after removal of hair and subcutaneous tissue were
weighed (and/or the area measured). They were saponified as for food
samples (except that only 5 mL instead of 10 mL 100 g/L of KOH was
used, and pyrogallol replaced ascorbic acid), and the same procedure
followed up to the drying after rotary evaporation. The dried samples
were taken up in the mobile phase of 0.6% isopropanol in hexane, and
no clean up procedures were used before the samples were
chromatographed. An Econosil silica column using an isocratic mobile
phase of 0.6% isopropanol in hexane at flow rate of 1 mL/min and
detector settings of 271 nm and AUFS (absorbance units full scale) of
0.05 was used. Mean ± SD recovery of 7-DHC added in
place of skin was 0.89 ± 0.07 which is comparable to that
reported by Takada et al. (1981)
.
25-Hydroxyvitamin D (25-OHD).
Plasma concentrations of 25-hydroxyvitamin D was measured by the
protein-binding assay described by Chen et al. (1990)
,
using either rat or cat binding protein. This assay does not
distinguish between 25-hydroxyergocalciferol and
25-hydroxycholecalciferol.
Experimental procedures.
Four experiments were conducted to investigate vitamin D synthesis in cats.
(i) Experiment 1.
In this experiment, the ability of kittens to synthesize vitamin D when
exposed to natural sunlight was tested. Nine newly weaned kittens were
given the vitamin D-free diet and divided into two groups of four
(control) and five (exposed) kittens. The control group was kept
indoors and received no exposure to UV light. The exposed group was
placed in a wire cage without shade and received full summer
(June-July) sun at Davis, CA (
38°N, L 121°W) from 0900 to
1200 h (summer time) for 5 d/wk. Exposed kittens had water, but no
food was available in this period, and were under continual
surveillance for hyperthermia. One kitten in the exposed group had the
hair clipped on its back to increase the area of skin exposed. All
kittens were housed in the same group cage except when one group was
exposed to sunlight.
(ii) Experiment 2. Four weaned male kittens were given the vitamin D-free diet and when their body weight was 1.23 ± 0.014 kg (mean ± SEM), they were randomly allocated to a control group of two kittens (no UV exposure) and a group that received 3 h/d exposure to UV lights (FS40 or FS60 fluorescent sun lamps supplied by Universal Light Source, San Francisco, CA) for 173 d. The efficacy of the lamps was confirmed by exposing vials containing alcoholic solution of 7-dehydrocholesterol and by measuring the formation of pre-vitamin D. Plasma concentration of 25-OHD was measured at intervals during the subsequent 173 d.
(iii) Experiment 3. Because vitamin D synthesis could not be demonstrated in experiments 1 or 2, the skin of cats and other animals was analyzed for 7-dehydrocholesterol, the precursor for vitamin D synthesis. The origins of the skin samples were as follows: 54 samples were taken from 14 normal cats killed in unrelated studies. Four skin samples were taken from two hamsters, nine samples from five rats, two each from the ears of two sheep and three each from the ears and udders of two sows. The hamsters and rats had previously been fed nonpurified diet (Rat Diet # 5012, PMI Feed Inc., St. Louis, MO); the sheep and sows had been sent from slaughter.
(iv) Experiment 4.
Ten male kittens were given the vitamin D-free purified diet at weaning
and continued to receive the diet until their plasma concentration
of 25-OHD was less than 5 nmol/L. Four pairs of cats were selected
based on skin color and divided into two groups. One group of cats
received the purified diet alone, while the other group of cats
received the purified diet to which 250 mg of BM 15.766
(4-[2-[1-(4-chlorocinnamyl)piperizin-4-yl]ethyl]benzoic acid)
Boehringer Mannheim GmbH Mannheim, Germany) was added/kg diet. The
compound BM 15.766 is an inhibitor of
7-dehydrocholesterol-7-reductase (EC 1.3.3.21) that
catalyzes the conversion of 7-dehydrocholesterol to cholesterol. All
eight cats had the hair clipped from the scapula to the tuber coxae and
about 5 cm down the lateral surface at weekly intervals. Pairs of cats
were housed in adjacent metabolism cages (61W x 61D x 90H
cm) so they were exposed to the same pair of fluorescent UV lamps
suspended immediately above their cages for 9 wk. During UV exposure,
food but not water was removed from the cages of all cats. Samples of
blood were taken at approximately weekly intervals and the 25-OHD
concentration measured. At the end of the 9-wk experimental period, a
mid-side skin biopsy was taken and the concentration of 7-DHC in the
skin was measured.
Analysis of potential prey of feral cats.
To determine if potential prey animals could supply the cat's dietary requirement for vitamin D, seven wild caught roof rats (Rattus rattus L.); three mice (Mus musculus) and two birds were analyzed. In addition, four laboratory-raised rats were analyzed for vitamin D content.
Statistical analysis.
A paired t-test was used to compare treatments in experiment 4. All values are mean ± SEM and a value of P < 0.05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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).This observation suggested that cats do not synthesize adequate amounts
of vitamin D from exposure to UV light to maintain plasma concentration
of 25-OHD. As the rate of decline in plasma 25-OHD was not slower in
the kitten with the hair shaved than those not shaved, it suggested
that limited exposure of skin to UV light was not the primary reason
for the lack of effective synthesis of vitamin D. One kitten from the
exposed group developed posterior paralysis that was subsequently found
to be associated with vitamin D deficiency in cats (Morris et al. 1994
).
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The concentration of total 7-DHC in the skin of cats and other species
is presented in Fig. 2
.Cats had very low concentrations of 7-DHC in their skin compared to
other species known to synthesize vitamin D. Therefore, in the
following experiment, a low concentration of 7-DHC was examined as a
cause of ineffective vitamin D synthesis in cats.
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).However, after 1 wk delay, cats receiving the inhibitor of 7-DHC
reductase in the diet and exposure to UV light had a steady increase in
concentration of 25-OHD in plasma, attaining levels that would be
regarded as normal in other species. However, cats not receiving the
inhibitor in the diet and exposed to UV light had no increase in plasma
25-OHD concentration. Cats receiving the inhibitor had concentrations
of 7-DHC in the skin that were five times that of cats in the control
group (P < 0.001) (Table 2
),indicating the inhibitor reduced the conversion of 7-DHC to
cholesterol, permitting effective vitamin D synthesis.
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Considerable variation in whole-body vitamin D occurred among
individuals, especially among the roof rats. Laboratory rats that had
been fed a commercial nonpurified diet had higher concentrations than
wild roof rats, which may reflect a dietary rather than a breed
difference. They also had less variation among individuals, which tends
to support diet as the primary determinant of individual vitamin D
content. The higher concentration of cholecalciferol in deer mice than
roof rats trapped at the same location was not anticipated, but could
be due to different feeding patterns of the two species.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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De novo sterol synthesis occurs in all animal tissues that have been
investigated, but the relative rates in individual tissues vary greatly
among species. In rats, monkeys and humans, the liver and intestines
appear to have the highest rates, but in pigs the intestine contributes
only a minor amount while the liver and adipose tissue account for 67
and 29%, respectively (Nes and McKean 1977
). There do
not appear to have been any studies on the pathway of cholesterol
synthesis in the skin of cats, but it would be reasonable to suggest
that the metabolic pathway first proposed by Kandutsch and Russell (1960)
from lanosterol to cholesterol would be the same
in cats as in other mammals.
While the inhibitor of 7-DHC reductase increased the concentration of
total 7-DHC in the skin fivefold and permitted vitamin D synthesis to
occur, some synthesis would be expected to have occurred from the
endogenous 7-DHC present in the untreated cats. An increase of
one-fifth of the final plasma 25-OHD concentration in the treated cats
(91 nmol of 25-OHD/L) would have been detected in the control cats. By
saponification, we measured the total 7-DHC, both in the free and
esterified forms. In rat skin, most (78–93%) of the 7-DHC is in the
esterified form (Takada et al 1981
). Possibly, the 7-DHC
in the untreated cats was in a conformational state that did not permit
it to be converted to pre-vitamin D, or the pre-vitamin D formed was
not free to be transported to the liver for hydroxylation to 25-OHD.
The absence of vitamin D from the diet of cats results in clinical
signs of deficiency, but the time before signs appear is related to
both the initial stores of vitamin D and the calcium level in the
vitamin D-free diet. In experiments not reported here, kittens from
queens receiving a diet containing 400 µg of cholecalciferol/kg
during pregnancy and lactation were given a vitamin D-free diet. These
kittens completed their growth phase (>26 wk of age) without clinical
signs of deficiency. Similarly, when weaned kittens were given a
vitamin D-free diet containing 14 g of Ca/kg dry matter, clinical
signs were either not expressed or delayed due to nonvitamin D-mediated
calcium absorption (Lee et al. 1991
).
Cats before domestication must have derived sufficient vitamin D from
their natural food to meet their needs. To assess the possibility that
diet could have supplied sufficient vitamin D, it is necessary to have
an estimate of the vitamin D requirement of cats. Earle et al. (1994)
and Morris et al. (1999)
reported that
kittens given purified diets containing 3.125 µg of
cholecalciferol/kg dry matter did not show clinical signs of vitamin D
deficiency when the diet had a high (12 g/kg of dry matter) calcium
centration, but the plasma concentrations of 25-OHD were below those
considered normal for other mammals. However, a diet with 6.25 µg of
cholecalciferol/kg resulted in plasma 25-OHD in excess of 50 nmol/L
(20ng/mL), which is regarded as adequate in humans (Holick 1990
). If this value is taken as adequate in cats, and the wild
trapped animals in Table 3
are representative of the diet of
pre-domesticated cats, the diet alone could supply sufficient vitamin
D. For cats consuming this diet of whole animals, the ability to
synthesize vitamin D is redundant. Ineffective synthesis of vitamin D
is the most recent example of the many nutritional peculiarities of
cats. This metabolic change has presumably occurred over the 35 million
years following the divergence of felids from the general fissipid
progenitors and has occurred in response to an all-animal tissue diet.
As administration of the inhibitor of 7-DHC reductase allowed vitamin D
synthesis to occur, it suggests that the activity of the 7-DHC
reductase is high, not that cholesterol synthesis is limited. To our
knowledge, no examples of high activity of 7-DHC reductase have been
reported in mammals, but in the frequently occurring human autosomal
recessive disorder known as Smith-Lemli-Opitz syndrome, there is
reduced/deficient activity of the enzyme (Salen et al. 1996
). The syndrome is caused by mutation in the gene coding
for 7-dehydrocholesterol-7-reductase (Waterham et al. 1998
) on chromosome 11q12-13 (Wassif et al. 1998
). Individuals with the syndrome have multiple congenital
malformations, elevated plasma levels of 7-DHC and low levels of
cholesterol; plasma cholesterol and 7-DHC concentrations are used for
the diagnosis of the syndrome. The deficiency of the enzyme has been
demonstrated in liver microsomal preparations and in cultured skin
fibroblasts from homozygous individuals (Honda et al. 1995
).
In addition to being a precursor of cholesterol, 7-DHC acts as a
feedback inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase
(Honda et al. 1998
), the rate-controlling enzyme in
cholesterol synthesis. Because as the level of 7-DHC in cat skin is
low, one would not expect 7-DHC to be an important feedback inhibitor
of cholesterol synthesis. We did not measure the cholesterol content of
cat skin, and this may be an important regulator of 7-DHC content, as
in human fibroblasts the mRNA encoding 7-DHC reductase is upregulated
in cultures that are grown in cholesterol-deficient medium
(Wassif et al. 1998
).
Neither the rate of cholesterol synthesis nor the activity of 7-DHC reductase has been reported in cats. However, the evidence suggests that consistent with the other known nutritional peculiarities of cats that can be related to changes in activities of enzymes, the ineffective vitamin D synthesis in cats is due to high activity of the 7-DHC reductase enzyme.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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7-reductase. Proceedings. pp.
721–722. 
2 Supported in part by a grant from the
George and Phyllis Miller Feline Health Fund, Center of Companion
Animal Health, University of California, Davis, CA.
3 Abbreviations used: 7-DHC, 7-dehydrocholesterol;
HPLC, high-performance liquid chromatography; 25-OHD, 25-hydroxyvitamin
D; UV, ultraviolet.
Manuscript received October 22, 1998. Initial review completed November 23, 1998. Revision accepted December 22, 1998.
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REFERENCES |
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Kandutsch A. A., Russell A. E. Preputial gland tumor sterols. III. A metabolic pathway form lanosterol to cholesterol. J. Biol. Chem. 1960;235:2256-2261
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Morris J. G., Earle K. E., Anderson P. A. Plasma 25-hydroxyvitamin D in growing kittens is related to dietary intake of cholecalciferol. J. Nutr. 1999;129:909-912
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23. Waterham H. R., Wijburg F. A., Hennekam R. C., Vreken P., Poll-The B. T., Dorland L., Duran M., Jira P. E., Smeitink J.A.M., Wevers R. A., Wanders R.J.A. Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene. Am. J. Hum. Genet. 1998;63:329-338[Medline]
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Webb A. R., Kline L., Holick M. F. Influence of season and latitude on the cutaneous synthesis of vitamin D3: Exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin. J. Clin. Endocrin. Metab. 1988;67:373-378
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