THE ACTION OF ETHANOLAMINE, METHYLETHANOLAMINE, AND DIMETHYLETHANOLAMINE ON LIPIDE

PHOSPHORYLATION*

BY CAMILLO ARTOM AND W. E. CORKATZER

(From the Department of Biochemistry, Bowman Gray School of Medicine, Wake Forest College, Winston-Salem, North Carolina)

(Received for publication, June 2, 1948)

The administration of a single dose of choline stimulates the formation of phospholipides in the liver (2,3) and in the small intestine (4) of rats on low protein diets. Like choline, ethanolamine is an essential constituent of phospholipides in tissues and one may suspect that it will exert a similar action. Moreover, choline can conceivably be formed by methylation of ethanolamine through the intermediate stages of methyl- and dimethyl- ethanolamine. There is already rather extensive evidence for the occur- rence of such a process in living organisms (5-ll), although, in t.his respect, considerable species differences were noted.’

In the present study the action of ethanolamine, methyl-, and dimethyl- ethanolamine on the formation of total phospholipides in the liver and small intestine has been investigated with the aid of radioactive phosphorus as an indicator.2 The results have been compared with those of simultaneous experiments in which an equivalent amount of choline was given. More- over, since apparently similar effects on the total phospholipides may ac- tually be the result of quite different actions on the individual phospholipide fractions, in a few experiments the separation of the choline-containing from the non-choline-containing phospholipides of the liver has been at- tempted, and the determinations have been carried out on the separated fractions.

Since the completion of our investigation, of which t,he main findings have been reported in summarized form (l), a paper by Platt and Porter (14)

* Aided by a grant from the John and Mary R. Markle Foundation. Preliminary reports (1) have been presented before the North Carolina Academy of Science, Wake Forest, May, 1947, the Seventeenth International Physiological Congress, Ox- ford, July, 1947, and the American Society of Biological Chemists, Atlantic City, March, 1948.

1 Unlike the rat (5) and a type III pneumococcus (6), the chick (12) and one mutant strain of Neurospora crassa (13,s) seem to be unable to carry out the conversion of ethanolamine into methylethanolamine.

* The P32 was supplied by the Clinton Laboratories, Oak Ridge, Tennessee, on allocation from the United States Atomic Energy Commission. Part of the methyl- and dimethylethanolamine used in the experiments was graciously offered by the Car- bide and Carbon Chemical Corporation, New York.

949

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950 ETHANOLAMINE AND LIPIDE PHOSPHORYLATION

has appeared concerning the action of ethanolamine on the rate of formation of phospholipides in the liver. On this point, their and our results are substantially in agreement.

EXPERIMENTAL

Male albino rat’s (100 to 110 gm.) were maintained for 7 days on a low fat, low protein diet (Diet 26 (3)) in which a solution of pure B vitamins (15) was incorporated daily. Some of the animals received a single large dose of a commercial preparation of salad oil 18 hours before death. Three to seven animals were used in each experiment. One of them was used as a control and received 1 cc. of water by stomach tube. The others received one dose of the substances to be tested (1 cc. of a 0.2 M solution of the chlorides by stomach tube).3 5 minutes later the rats were injected intra- peritoneally with a solution of Na2HP04 (10 to 20 y of P) containing 2 to 4 microcuries of radioactive phosphorus and after 6 hours they were killed by decapitation. The lipides were extracted from the liver and the small in- testine and their radioactivity and phosphorus content determined. The analytical procedures and the method for calculating and expressing the results have been described (3).

For the separation of the choline-containing from the non-choline- containing phospholipides, the chloroform solution of the lipides extracted from one or more livers was used. After evaporation of the solvent, the residue was dissolved in methanol, and the solution filtered and treated according to Taurog et al. (16). The radioactivity, phosphorus, and often also choline (17) were determined in aliquots of the solution before and after adsorption on MgO.

Results

The data on the radioactivity and specific activity of the total phospho- lipides in the liver and small intestine are reported in Tables I and II. In order to evaluate the statistical significance of our results, t.he differences observed in each experiment between the rats receiving the substances and the control receiving water have been averaged and the t test of sig- nificance (18) applied to the averages.4 The mean increase over the con- trols, the value of t, and the degree of probability (P) for a chance occurrence of the increase are indicated in Tables I and II.

3 Ethanolamine (Eastman Kodak), methylethanolamine (Carbide and Carbon Chemical Corporation), dimethylethanolamine (Carbide and Carbon Chemical Cor- poration, Eastman Kodak). These substances were ident,ified by determinations of specific gravity, boiling point, acid equivalent, ammonia evolved by alkaline pe- riodate, and form01 titration. The titer of the solutions of choline chloride (Merck and Company) was estimated by determinations of N and Cl.

4 Substantially the same conclusions are reached if the statistical treatment is applied to the differences between the means of each experimental group.

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C. ARTOM AND W. E. CORNATZER 951

TABLE I Total Radioactivity and Specific Activity of Phospholipides in Liver of Rats Receiving

Water, Ethanolamine, Methylethanolamine, Dimethylethanolamine, and Choline*

Total radioactivity Specific activity - ;i 3 ::

sg cd- 3 -

86 86 81 85

106 - 86

102 78 93

96

96

Loo 85 -

(ii

-

-

--

--

_ -

1

< -

1.134. 428 465 462

559

Experiment NO.

133 96

107

. -

_ _

-

-

It 2t 3t

4t

1.1.11.

281 426 291 385 408

307 373 306 352

534

402

439 482

r.1.u.

592

7.1.1(.

581 803

734

l.r.u.

586 485 495

542 729

394 500

748

579 475 433 513

930

705 485 (705 (463:

316 7.2:

:o.o

119 4.1!

:o.o:

126 128 102

132

123 147

159

119 144

179

179 164 122

142

163

95 148 -

141 (148:

46 3.01

CO.Of

143 (143

53 9.3:

:o.o 1 is -

421 496 626 429 558

500 547 680

115 126 135 150 152

118 140 141

130 (1341

37 8.8!

:o.o:

103 104

115 121 106

110 010)

19 4.39

:0.01

9

10

11 12

636

823 644 535

575

635 0343:

183 4.61

co.01

Averages# . . . . .

Mean increase over controls

t . . . . . . . . . . . . . . . P . . . . . . . . . . .

383 (398

514 (53%

147 6.8!

:o.o:

* The radioactive values are expressed in relative radioactive units (r.r.u.), the dose of P52injected into the rat being considered as 104 r.r.u. “Total radioactivity” is the number of r.r.u. in the lipides of the whole organ. “Specific activity” is the ratio of the total radioactivity to the mg. of lipide phosphorus in the organ of a 100 gm. rat. t is the test of significance as applied to the mean increase over the control of the same experiment. P is the degree of probability for a chance occurrence of this increase.

t These rats received 1.5 gm. of oil 18 hours before death (12 hours before receiving P39.

$ The figures in parentheses are the averages of the values obtained on the rats to which no oil was given.

It is apparent that, in the liver of the rats fed any of the substances tested, both the radioactivity and the specific activity are markedly in-

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952 ETHANOLAMINE AND LIPIDE PHOSPHORYLATION

creased and that all the increases have a considerable degree of statistical significance.

On the basis of the average values, the stimulating effect on the lipide phosphorylation in the liver is increasing in the order, choline, ethanolamine, methyl-, and dimethylethanolamine.

TABLE II

Total Radioactivity and Specijic Activity of Phospholipides in Small Intestine of Rats Receiving Water, Ethanolamine, Methylethanolamine, Dimethylethanolamine, and

Choline*

Total radioactivity Specific activity

I.I.U.

184 206 179

156

Experiment No.

45 61 61 59 61

52 55 55 41

51

51

65 58

55 :53;

-

1.7.u.

229 236 181

69 64 58

60 64

67 66 76

(it!,

9 3.10

:0.05

1* 2* 3*

4*

I.T.U.

125 213 226 194 199

_- .-~

5 6 7 8

120 161 160 109

9 88

10 167

11 210 12 216

Average*. . . . . .

Mean increase over controls

t . P .

168

(1541

I.l.Y.

224 261

239

59 74 57

66 I- -

)

< -

124 222 206 116 168

172 167 198

184 185

160 183 250

201 (192

23 1.51

>o.o:

52 77 70 48 60

60 63 66

214 191

128

171 124 211

131

215

208 257

68 70

70

74

79

58

70 76 71

61

174 (171

9 0.8:

>O.O<

172 (168:

27 1.8t

>O.O!

216 (201 (ii)

9 3.51

:o.o

)

3 5: -

5 j<

I

6 l<

* See explanations for Table I.

Essentially similar effects have been observed in many, but not in all, experiments on the small intestine. Accordingly, the mean increases over the controls, especially for the total radioactivity, are often small and always less marked than in the liver. However, all the differences in the specific activity values are clearly significant. In this respect, it should be

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C. ARTOM AND W. E. CORNATZER 953

pointed out that our determinations on the small intestine have been made on the whole organ, i.e. on both mucosa and muscle. In the latter tissue, the rate of phospholipide turnover is lower and perhaps it is modified to a lesser degree (or not at all) by the substances given to the animals.

From the limited number of data available, it seems that the administra- tion of oil 18 hours before death did not affect appreciably these results either in the liver or in the intestine.5

Table III shows the results of determinations made in order to test the reliability of the method for the separation of the choline- and non-choline-

TABLE III

Total,” Choline-Containing,t and Non-Choline-Contuining$ Phospholdpides of Rat Liver before and after Adsorption on MgO

Substance given jample

--

Water

Ethanolamine

Methylethanol- amine

Dimethyl- ethanolamine

Choline

A B C D E F G II I J K L

Before adsorption

Total phos- jholip.

ide

w.

104 83

109 82

105 84 92 94

102 74 84 86

holine mtsin

ing phos-

‘hi2!p-

mg. 51 44 51 41 56 44 53 49 59 41 64 62

- - Ratio,

choline- contain- ing to x total

0.49

0.53 , 0.47 0.50 0.53 0.52 0.58 0.52 i 0.58 / 0.55 / 0.76 j 0.72 I

After adsorption

Total phos- )holip

ide

w.

66 58 61 51 66 49 59 52 65 46 58 61

- ‘C cc

F

- holine mtain

ing phos- , Iholip-

ide

mg.

48 -I-

41 48 39 53 41 52 48 57 42 6.0 61

-

Ratio, choline- :ontain- ing to total

0.73 0.71 0.79 0.76 0.80 0.84 0.88 0.92 0.88 0.91 1.03 1.00

Choline- mtaininl phospho- ipide ml adsorbed

per ccst 94

93

94

95

95

93

98

98

97

102 94 98

-

r c : 1

NOW choline- ontainiw >hospho-

lipide rdsorbed

fiGI cent

66 56 78 61 72 80 82 91 81 86

100 100

__.- * Total phospholipide = mg. of lipide P X 22.7. t Choline-containing phospholipide = mg. of choline X 6.7. $ Non-choline-containing phospholipide = (mg. of t’otal phospholipide) - (mg.

of choline-containing phospholipide).

containing phospholipides in our lipide extracts. On the basis of the cho- line values, it appears that, after treatment with MgO, practically all of the choline-containing phospholipides (93 to 100 per cent) are left in the solu- tion. However, the amount, of phosphorus which escaped adsorption is

6 However, in four out of five experiments the intestine of the control rats which had received oil exhibited values for the total radioactivity (and, to a lesser extent, also for the specific activity) which were higher than the general averages. Similar increases in the intestinal lipides of rats on Diet 26 after the administration of a large dose of oil 6 hours before death have been noted previously (3).

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954 ETHANOLAMINE AND LIPIDE PHOSPHORYLATION

often greater than that which would have been expected from the choline figures, this excess representing from 9 to 44 per cent of the non-choline- containing phospholipides assumed to be present in the original extract. All of the non-choline-containing phospholipides seem to have been ad- sorbed only in the two experiments on the liver of rats which received choline. In these experiments the ratio of choline to phosphorus in the solution after adsorption approximates 1, as in the determinations of Taurog et al. (16). These findings suggest the possibility that, when cho- line or choline precursors are absent from the diet, increased amounts of

TABLE IV Total Radioactivity and Specifk Activity of Rat Liver Phospholipides in Fractions Not

Adsorbed and Adsorbed by MgO*

Substance given

Water (controls). . . . .

Ethanolamine . . .

Methylethanolamine. . .

Dimethylethanolamine.

Choline.. . . . . .

-

1 at

-

h of mlyse

-

s ’

-

Not adsorbed :choline-containing

phospholipide)

227 f 8 (91 f 9) 310 f 46

(131 f 25) 328 3t 14

(133 f. 3) 416 f 49

(156 f 39) 318 f 15

(118 f 8)

-

Adsorbed (non- choline-containing

phospholipide)

141 zk 12 (92 f 29) 218 f 21

(127 f 12) 205 z!z 6

(128 It 13) 186 f 17

(127 -f 6) 149 * 19

(115 f 9)

- Per cent increase over

controls

Choline ontain,

ing phos-

)holip- ide

(.)

* The figures preceded by the f sign indicate the standard deviations. The values in parentheses are those of the specific activity. For other explanations see Table I.

substances containing phosphorus, but not choline, may be present in the lipide extracts of the liver and, like lecithin, remain in the methanol solution after treatment with MgO. This hypothesis is now being investigated. At present, it is apparent that, at least in most of our experiments, the sig- nificance of the results obtained by the procedure which we have used is open to question. With this reservation, in Table IV we have merely recorded the average data of these determinations and their standard devia- tions. After the administration of ethanolamine, methyl-, and dimethyl- ethanolamine, the radioactivity values in both phospholipide fractions were consistently higher than the corresponding values in the controls receiving

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C. ARTOM AND W. E. CORNATZER 955

water. In the group receiving choline, the radioactivity was definitely elevated only in the choline-containing fraction.

When the changes in the radioactivity of the two fractions are compared with each other, the absolute increase was always higher in the choline- containing phospholipides. However, the per cent increase over the control value was greater in the non-choline-containing fraction after ethanolamine was given, and was approximately the same in the two fractions from the rats receiving methylethanolamine. On the other hand, the increase was proportionately higher in the non-choline-containing phospholipides after dimethylethanolamine was given, and, even more so, after choline ad- ministration.

As for the specific activities, in all experimental groups the values were higher than in the controls, in the choline-containing as well as in the non- choline-containing phospholipides. Except for the rats receiving dimethyl- ethanolamine, the average figures were of the same order of magnitude in the two fractions. However, the individual data were quite irregular, and in the various experiments of the same group the specific activity was some- times greater in the choline-containing and sometimes in the non-choline- containing fraction.

In view of these inconsistencies, it is not easy to state definitely whether or not any of the substances which we have tested stimulated preferentially the formation of lecithin or of cephalin. Indeed, under the conditions of our experiments, it seems that the evidence for a proportionately greater formation of one phospholipide fraction would be conclusive only if the per cent increase in the total radioactivity of this fraction were greater and if the specific activity were also consistently higher or, at least, not lower than that of the other fraction. However, it must be pointed out that, because of the likely presence in the lipide extracts of variable amounts of P-containing substances other than the typical lecithin and cephalin (see above), the computation of the specific activity in the separated fractions was probably subject to an error greater than that of the radioactive deter- minations. On the other hand, if lecithin and cephalin were synthesized in the liver from a common immediate precursor containing P (e.g. glycero- phosphate or phosphatidic acid), the comparison between the radioactivity values would be a direct indication of the relative amounts of phospholipides newly formed in the two fractions.

DISCUSSION

Present findings show that in both liver and intestine of rat,s on a low

fat, low protein diet the administration of a single dose of ethanolamine or of its products of partial methylation stimulates the formation of total phospholipides. The stimulation appears to be of the same order of magni-

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956 ETHANOLAMINE AND LIPIDE PHOSPHORYLATION

tude or greater than that caused by the administration of an equivalent amount of choline.6

The effect of choline on lipide phosphorylation in the liver has been corre- lated with the action of this substance in preventing fatty liver (and hemor- rhagic kidneys in weanling rats). Other lipotropic substances such as betaine (19) and methionine (20) also cause an increase in the formation of total phospholipides in the liver. Dimethylethanolamine, which in the present experiments stimulated markedly the lipide phosphorylation, was previously found to be lipotropic (7). On the other hand, ethanolamine is said to be ineffective (21, 22), although in very young rats the administra- tion of this substance, alone or together with methionine, to a certain extent decreases the fat infiltration (23,24) and prevents hemorrhagic kidneys (24). An even more definite lack of parallelism between stimulation of lipide phosphorylation in the liver and lipotropic activity has been noted for cysteine and cystine (20). In other words, from the present evidence, it appears that those substances which exert a marked lipotropic action also stimulate the formation of liver phospholipides, but that the reverse is not true. Apparently, the lipotropic action is more specific than the stimula- tion of lipide phosphorylation.

As mentioned above, the adequacy of the separation of the choline-con- taining and non-choline-containing phospholipides i open to question, and a further uncertainty in the interpretation of the data is introduced by the irregularity in the specific activity values as determined in the separated fractions. If it were assumed that in the conditions of our experiments the radioactivity data may be a reliable indication of the relative amounts of choline- and non-choline-containing phospholipides formed during the 6 hours of the experiments, it would appear that, after choline was given, the stimulation of lipide phosphorylation in the liver involves almost exclu- sively the choline-containing fraction, a finding which would be in line with previous results of Entenman et al. (25) on the liver of dogs receiving cho- line. On the other hand, after ethanolamine or its partially methylated derivatives were fed, the formation of both lecithin and cephalin is in- creased, but the extent of the relative increase in each fraction varies with the substance given.

As a tentative explanation of these findings, it may be pointed out that the protein level in our experimental diet was as low as 5 per cent, and that casein contains only minute amounts of glycine, a likely precursor for ethanolamine (5). In spite of the easiness with which glycine can be syn-

6 However, it should be pointed out that, according to our previous data (3), the choline effect on lipide phosphorylation in the liver and intestine of rats on Diet 26 is markedly enhanced by the simultaneous administration of fat.

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C. ARTOM AND W. E. CORNATZER 957

thesized in the body, it is perhaps not unreasonable to assume that in our control rats the availability of ethanolamine, as well as that of choline, could represent a limiting factor for the synthesis of phospholipides. When large amounts of preformed ethanolamine were administered part of the substance given may have been utilized directly as a building stone for the formation of cephalin, and another part indirectly as a methyl acceptor for the synthesis of choline. One can thus understand that in these experi- ments an increased formation of both phospholipide fractions occurred, the synthesis of lecithin being then limited only by the amounts of available methyl groups. After methyl- or dimethylethanolamine was given, a more marked synthesis of lecithin became possible, since for each newly formed molecule of choline, only two, or one, additional methyl groups were re- quired. When large amounts of choline are fed, it is probable that part of the choline reaching the liver is destroyed by the action of choline oxidase (26, 27) and thus is not used in the synthesis of phospholipides. On the other hand it is possible that dimethylethanolamine is introduced as such into the molecule of a phospholipide (or a phospholipide precursor) without previous methylation to choline, and by this process escapes the action of choline oxidase. This might perhaps explain the higher rate of lecithin formation after dimethylethanolamine is given than after choline ad- ministration.

As for the finding that not only ethanolamine but also its products of partial methylation caused an increase in the radioactivity of the non- choline-containing fraction, it is conceivable that in these experiments some ethanolamine originated from the compounds fed. Such a demethylation should probably occur through reactions other than those involved in transmethylation, since dimethylethanolamine apparently is not an effec- tive methyl donor for the synthesis of methionine (7, 28). On the other hand, if the possibility of a direct introduction of partially methylated ethanolamine in the phospholipide molecule is accepted, such atypical phospholipides may be partly adsorbed on MgO and thus give higher values in the cephalin fraction. It is obvious that the speculations outlined above are merely working hypotheses and that a number of alternative explana- tions may be suggested.

SUMMARY

Rats maintained on a low casein, low fat diet were given by stomach tube a single dose of ethanolamine, methylethanolamine, dimethylethanolamine, or choline. The controls received water. The animals were then in- jected with isotopic phosphate and the radioactivity and the phosphorus content determined in the lipides of the liver and small intestine.

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958 ETHA4NOLAMINE AND LIPIDE PHOSPHORYLATION

All the substances tested stimulated the formation of total phospholipides in both tissues. The stimulation by ethanolamine and by the products of its partial methylation was of the same order of magnitude or greater than that observed after choline was given.

In a number of experiments the liver phospholipides have been separated into choline-containing and non-choline-containing by adsorption on mag- nesium oxide. Under the conditions of the present experiments, the ade- quacy of the separation and the significance of the results obtained on the separated fractions are somewhat doubtful. To the extent of their reliabil- ity, these results showed that after ethanolamine, methyl-, and dimethyl- ethanolamine were given, the radioactivity was increased in both phospho- lipide fractions, but the extent of the relative increase in each fraction varied with the substance administered. After choline was given, the in- crease was confined to the choline-containing phospholipides.

BIBLIOGRAPHY

1. Artom, C., and Cornatzer, W. E., J. Elisha Mitchell SC. Sot., 63, 93 (1947); Abstr. Communicat. XTrIZ Internat., Physiol. Cong., Oxford, 56 (1947); Federation Proc., 7, 143 (1948).

2. Perlman, I., and Chaikoff, I. L., J. Biol. Chem., 127, 211 (1939). 3. Artom, C., and Cornataer, W. E., J. Biol. Chem., 171, 779 (1947). 4. Artom, C., and Cornatzer, W. E., J. BioZ. Chem., 165, 393 (1946). 5. Stetten, D., Jr., J. BioZ. Chem., 140, 143 (1941). 6. Badger, E., J. BioZ. Chem., 158, 183 (1944). 7. du Vigneaud, V., Chandler, J. P., Simmonds, S., Moyer, A. W., and Cohn, M.,

J. Biol. Chem., 164, 603 (1946). 8. Jukes, T. H., Oleson, J. J., and Dornbush, A. C., J. Nutr., 30. 219 (1945). 9. Jukes, T. H., Dornbush, A. C., and Oleson, J. J., Federation Proc., 4,157 (1945).

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C. ARTOM AND W. E. CORNdTZER 959

24. Abdon, N. O., and Borglin, N. E., ActapharmacoZ. et tozicol., 3.73 (1947). Borg- lin, N. E., Acta pharmacol. et tozicol., 3, suppl. 1 (1947).

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Camillo Artom and W. E. CornatzerLIPIDE PHOSPHORYLATION

DIMETHYLETHANOLAMINE ONMETHYLETHANOLAMINE, AND

THE ACTION OF ETHANOLAMINE,

1948, 176:949-959.J. Biol. Chem. 

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