THE CONVERSION IN VIVO OF XYLITOL TO GLYCOGEN VIA THE PEKTOSE PHOSPHATE PATHWAY*

BY DONALD B. McCORMICKt AND OSCAR TOUSTER

(From the Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee)

(Received for publication, June 17, 1057)

Studies in this laboratory designed to elucidate the metabolism of L-xylulose, the characteristic urinary sugar of essential pentosuria, have shown that n-glucuronolactone is a precursor of the ketopentose in guinea pigs and in humans (1, 2) and that there are enzymes in guinea pig liver which can interconvert L-xylulose and xylitol as well as xylitol and D-xylu- lose (3, 4). The discovery that n-xylulose 5-phosphate is an intermediate in the pentose phosphate shunt (6-phosphogluconate oxidation pathway) (5, 6) suggested that glucuronate and the xyluloses might be ultimately metabolized via this pathway (4, 7). A kinase has indeed been found in calf liver which can convert n-xylulose to n-xylulose 5-phosphate (8). These findings suggest that the following sequence of reactions occurs in mammals: n-glucuronate --) L-xylulose G= xylitol ti n-xylulose + D-xylu- lose 5-phosphate.

Since the formulation of this sequence is based upon work done on different species and partly on enzymatic studies performed in vitro, it seemed desirable to obtain evidence in tivo regarding its physiological occurrence. The tracer experiments reported elsewhere (2) have demon- strated the conversion of n-glucuronolactone to L-xylulose in a pentosuric human through reactions involving loss of the carboxyl carbon of the former compound, with the aldehydic carbon becoming the fifth carbon of the pentose. The present paper reports a study of the metabolic fate of a compound which is intermediate in the reaction sequence shown above. Xylitol-l-Cl4 was chosen because it can be conveniently prepared from the readily available n-xylose-1-CY4. n-Ribose, known to be metabolized via the pentose phosphate shunt (9), and n-xylose were tested for compara- tive purposes. A recent report has shown that the latter is also metabolized via this pathway (10).

It was first demonstrated that xylitol is oxidized in vivo to carbon dioxide. A study was then undertaken to determine whether the distribution of

* This work was supported in part by a grant from the National Science Founda- tion.

t Predoctoral Fellow of the National Institute of Arthritis and Metabolic Diseases, Public Health Service (1957-58).

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452 XYLITOL METABOLISM

CY in the glucose of liver glycogen formed from injected xylitol-1-C” would conform with the pattern expected from metabolism of the polyol via the pentose phosphate shunt.

EXPERIMENTAL

Methods-Adult Sprague-Dawley albino rats and adult albino guinea pigs, maintained on a Purina chow diet, were injected intraperitoneally with 1 ml. of water containing 2.0 to 6.7 PC. (10 to 15 mg.) of n-xylose-l- Cl4 or xylitol-1-C”. These animals were placed in a metabolic apparatus for trapping the expired CO2 as Na2C03, to be plated and counted as BaC”Oa, and for collecting urine during a 24 hour period.

For the liver glycogen studies, another group of animals was fasted for 24 hours before oral administration of 1.5 to 4.0 ml. of 50 per cent glucose solution followed, after approximately 15 minutes, by intra- peritoneal injection of 1 ml. solutions of 1.06 to 6.70 PC. (5.4 to 25.0 mg.) of n-ribose-l-C14 or xylitol-l-C14. After 2 hours, they were killed by cervical fracture and decapitated, and the livers were extirpated and plunged into hot, 30 per cent KOH.

Glycogen was isolated by the method of Good, Kramer, and Somogyi (11) and precipitated twice from 60 per cent ethanol. After removal of an aliquot for counting, the remainder of the glycogen was hydrolyzed to glucose by Ha04 essentially as described’by Topper and Hastings (12), with carrier glucose being added. The isolated, crystalline glucose was degraded by a combination of methods which gave directly the Cl4 content of the carbon atoms in the chain. Carbon 1 was obtained as carbon dioxide after conversion of glucose to potassium gluconate by the method of Moore and Link (13), followed by periodate oxidation according to Eisenberg (14). Then the residue was treated with dimedon to isolate the formaldehyde produced from carbon 6, the dimedon product being counted after plating. Carbon 2 was derived from degradation of n-glucobenzimidazole to 2-ben- zimidazolecarboxylic acid, followed by decarboxylation of the latter as described by Bernstein et al. (15). Carbon 3 was obtained as formate from periodate oxidation of methyl ci-n-glucopyranoside as described by Wood, Lifson, and Lorber (16). This formate was refluxed with HgO for conversion to carbon dioxide. Carbons 4 and 5 were obtained to- gether by refluxing with HgO the formate residue from periodate oxidation of n-glucosazone, as in the procedure of Topper and Hastings (12).

For substantiation of the results obtained by the above methods, the following procedures were also employed. Carbons 1 and 2 were deter- mined together by combustion of the 2-benzimidazolecarboxylic acid. Subtraction of the directly obtained value for carbon 2 (from decarboxyla- tion of the acid) gave carbon 1, and subtraction of the directly obtained

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D. R. MCCORMICK ASD 0. TOUSTER 453

value for carbon 1 (from decarboxylation of the potassium gluconate) gave carbon 2. The mesoxaldehyde 1,2-(bis)phenylhydrasone derived from periodate oxidation of n-glucosazone yielded a value for carbons 1, 2, and 3 together, from which each of the three individual carbons was obtained separately by subtraction of the other two carbons. By appro- priate summations and then subtraction from 100, several independent values were derived for various carbon atoms and compared with the “direct” methods. Since no significant discrepancies were found, only the directly determined values are given in this paper.

Combustions were carried out by the method of Thorn and Shu (17). BaC’403 was the material counted except as noted for carbon 6. All samples were counted in a windowless gas flow counter with corrections being made for thickness of material.

Materials-n-Ribose-l-C*4 and D-XylOSe-1-CL4, purchased from the National Bureau of Standards, had specific activities of 0.40 and 0.67 PC. per a., respectively. Xylitol-l-Cl4 was obtained by a Raney nickel reduction of n-xylose-l-Cl4 as described previously for unlabeled polyol (4, 18). The labeled polyol was purified by repeated crystallization from absolute ethanol until the melting point as determined on a Fisher-Johns melting point apparatus was sharp and higher than 91’ (usually, 92-93’). Over-all yields were about 55 per cent of theoretical, starting with 100 mg. of n-xylose-1-C4. The preparations showed a single periodate-positive spot on ascending paper chromatograms, with n-butyl alcohol-glacial acetic acid-water (4: 1: 5, upper phase) as solvent; no naphthoresorcinol- positive material was present.

The rats were purchased from Sprague-Dawley, Inc., of Madison, Wis- consin, and the guinea pigs from Carworth Farms, Inc., of New City, New York. The weight and sex of each animal are noted with the experimental data.

Results

Table I presents the values for the per cent of the administered doses of xylitol and n-xylose eliminated in the urine and as expired COZ. The time courses of expiration of C’402 in these experiments are shown in Fig. 1. Rapid peaking of Cl4 activity at about 2 hours occurred with both xylitol and n-xylose, followed by a fairly rapid decrease and a slower return to background. While the plot of the specific activity of expired Cl402 against time gives information as to the rate of oxidation of the compounds, Fig. 2 gives a better graphic depiction of the extent of oxidation. These experiments demonstrated that xylitol was as efficiently oxidized to COZ in the intact animal as was n-xylose. Furthermore, the data in Table I indicate that most of the remaining CL4 activity in the xylose experiment,

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454 XYLITOL METABOLISM

but not in the xylitol experiment, can be accounted for in the urine. How- ever, it should be pointed out that great variation in renal threshold for a particular compound has been observed among animals of the same species and strain (19).

That a portion of the administered xylitol-1-V was present in the urine was suggested by the following experiment: A 10 ml. aliquot of a

TABLE I Urinary and Respiratory Elimination of Cl4 from D-Xylose-1-C” and Xylitol-1-P

Substance administered Experimental animal

n-Xylose-I-CY (6.7 pc., 10 mg.) Guinea pig, o (397 gm.) Xylitol-1-P (2.0 PC., 15 mg.) “ “ 0 (315 gm.) n-Xylose-1-C” (6.7 PC., 10 mg.) Rat, ~9 (306 pm.)

Per cent administered 0’ eliminated in 24 brs.

15 75 10 25 11

FIQ. 1. Rate of conversion of xylitol-1-C I4 and n-xylose-1-C” to respiratory C1’01. Conditions as in Table I and as described under “Methods.” 0, xylitol- 1-W in the guinea pig; A, n-xylose-1-C” in the rat; 0, n-xylose-1-C” in the guinea pig. CYOz expressed as counts per minute per 38.2 mg. of BaWOa.

24 hour urine specimen from a guinea pig which had received xylitol-1-C” was acidified to release COZ, which was trapped and counted as BaCL40a. The activity of the latter showed that approximately 1.5 per cent of the Cl4 activity in the urine was in the form of bicarbonate. This acidified urine was then deionized over columns (1 X 25 cm.) of Amberlite IR- 120(H+) and Duolite A-4 (C08-), concentrated by distillation under a vacuum, and applied to Whatman No. 1 filter paper for ascending chroma- tography in n-butyl alcohol-glacial acetic acid-water (4: 1: 5, upper phase).

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D. B. MCCORMICK AND 0. TOUSTER 455

With internal and external xylitol standards, there was found at the proper position radioactive material which was positive to periodate-benzidine

HOURS

FIQ. 2. Extent of conversion of xylitol-l-04 and n-xylose-l-C’*’ to respiratory C”0,. The experimental conditions and the symbols are the same as those in Fig. 1.

TABLE II Distribution of Cl’ in Carbons 1 and 6 of Liver Glycogen after Administration

of o-Ribose-1 -Cl4 and Xylitol-1 -Cl’

Substance injected

n-Ribose-l-CL4 (2.01 PC., 5.4 mg.).......................

Xylitol-l-U4 (1.06 PC., 9 mg.).

“ (3.75 pc., 25 mg.)

“ (1.18 pc., 10 mg.) “ (3.75 PC., 25 mg.)

-

c 50 per

:ent glu- cose fed

ml.

1.5

1.5

4.0

1.5 3.0

-

.-

Experimental animal*

Guinea pig, 9 (425 pm.)

Guinea pig, 9 (410 pm.)

Guinea pig, 0 (460 gm.)

Rat, d (4% gm. ‘( 0 (329 “

Admin- istered C’a in

clycogen

-

46.1 2.0

37.6 1.7

44.3 1.7

38.9 1.4 37.4 1.3

cdrbon hwn 6t

* Weights of animals before 24 hour fasting period. t Carbons 1 and 6 were calculated with reference to n-glucose-Cl4 as a 100 per cent

base. Procedures as under “Methods.”

dip reagent (20) and negative to naphthoresorcinol spray reagent (21). Thus C4-pentitol, presumably xylitol-1-C14, was present in the urine.

Table II summarizes preliminary experiments on the conversion of xylitol-l-Cl4 and of n-ribose-1-C” to liver glycogen. It is evident that the pentitol is an efficient glycogen precursor. Degradation of the glucose

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456 XYLITOL METABOLISM

chains to determine the Cl4 content of carbons 1 and 6 gave values in agree- ment with those expected if the administered substances had been metabo- lized via the pentose phosphate pathway (see under “Discussion”).

Experiments were then performed to obtain values for the entire hexose chain of glycogen. Two changes in procedure were made. First, the same glucose dose was administered regardless of weight or species of animal. Second, potassium n-gluconate was oxidized to BaC*40a to serve as the 100 per cent base for expression of the relative per cent incorporation of radio- isotope into carbon 1. We had previously found that the gluconate may give higher values than isolated, recrystallized glucose used as the base.

TABLE III

Distribution of Cl4 in Liver Glycogen after Administration of D-Ribose-i-C14 and Xylitol-1-C”

Per cent Relative per cent C*’ of

Substance injected Experimental animal . administered glucose carbon atomt No. Cl1 in

glycogen 1 2 3 4-l-5 6 ---~~

n-Ribose-l-C14 (4.30 PC., Rat, 0 (356 7.1 69.5 2.4 28.5 2.9 1.4

10.4 mg.) gm.) Xylitol-1-C’” (6.70 Ire., Guinea pig, 0 23.8 67.1 0.4 25.6 2.0 2.1

10 mg.) (765 gm.) Xylitol-1-C” (6.70 PC., Rat, d (474 11.8 67.1 0.6 25.1 2.2 3.3

10 mg.) t3m.l

* Weights of animals before 24 hour fasting period. Each animal was given 2.0 ml. of 50 per cent glucose per 08.

t Carbons 1, 2, and 6 were calculated with reference to Cl”-potassium n-gluconate as a 100 per cent base; carbon 3 was based on Ci4-methyl cy-n-glucopyranoside as 100 per cent; carbons 4 and 5 were based on Cl4-n-glucose as 100 per cent. Procedures as described under “Methods.”

Moreover, gluconate was the logical reference substance, since it was the direct source of the CO2 of carbon 1. Table III summarizes the complete degradation experiments on xylitol and n-ribose. The agreement between the two substances is excellent, and the results are wholly in harmony with involvement of the pentose phosphate pathway. Furthermore, examina- tion of the xylitol experiments in Table III, as well as those in Table II, shows that the rat and the guinea pig behave similarly, indicating that the same general pathway is operative to approximately the same extent in both species.

DISCUSSION

The experiments reported demonstrate that xylitol is an efficient pre- cursor of liver glycogen in the rat and in the guinea pig. The efficient

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D. R. MCCORMICK AND 0. TOUSTER 457

utilization of the polyol is also indicated by the rapid and considerable combustion to Con.

Xylitol can be converted to n-xylulose not only by the mitochondrial enzyme previously mentioned (4) but perhaps also by the polyol dehydro- genase in the non-particulate fraction of liver (22, 23). Since it is likely that the kinase of Hickman and Ashwell (8) would convert the n-xylulose to n-xylulose 5-phosphate, it should be possible to predict the labeling in the liver glycogen. Xylitol-l-Cl4 chemically synthesized from D-xylose-l-Cl4 should yield a labeling pattern similar to n-ribose-l-C14. It should be noted that xylitol, like such compounds as citric acid and glycerol, contains a “meso carbon atom” (24), and if the xylitol had been made from n-xylose- l-C14, the expected Cl4 distribution in glycogen should conform with that derived from a carbon 5-labeled pentose. The suggestion by Horecker et al. (9) that 3 molecules of D-ribose-l-Cl4 should be converted to 1 mole- cule of unlabeled triose and to 2 molecules of glucose containing two- thirds of the isotope in carbon 1 and one-third in carbon 3 was borne out by their experiments with n-ribose-l-Cl4 by using rat liver enzymes. However, Katz et al. (25) found that glucose formed from D-ribose-1-C” by rat liver slices was approximately equally labeled in carbon 1 and in carbon 3. Furthermore, Hiatt (10) reported that an even greater degree of label- ing of carbon 3 occurred in tivo in mice. Whereas Katz suggested that the higher values in carbon 3 may result from a failure of tetrose phosphate to serve as a glycolaldehyde acceptor, Hiatt proposed that fructose 6-phosphate, rather than n-xylulose 5-phosphate, may serve as glycolalde- hyde donor in the formation of sedoheptulose 7-phosphate. The availa- bility of hexose in the intact animal served as a basis for the latter explana- tion, and Hiatt presented experimental results consistent with this view. His findings on n-xylose and n-ribose are also consistent with the view that the labeling pattern will reflect the relative rate at which a test substance is converted to an active glycolaldehyde acceptor or donor (10).

The labeling pattern of glycogen isolated after administration of xylitol- l-Cl4 is in essential agreement with the prediction based upon successive conversion of the polyol to n-xylulose and n-xylulose 5-phosphate, with subsequent conversion to hexose via the pentose phosphate pathway. The similar labeling obtained from n-ribose-l-C14 adds support to the xylitol experiments. The fact that ribose first becomes a glycolaldehyde acceptor (n-ribose 5-phosphate) and xylitol first becomes a glycolaldehyde donor (n-xylulose 5-phosphate) was not reflected in our results.

There now appears to be sufficient evidence for the formulation of a new carbohydrate pathway in mammals by which glucose can be oxidized and at least one essential metabolite, L-ascorbic acid, produced. n-Glucose is a precursor of the n-glucuronic acid moiety of glucuronides (26-Z@, and n-glucuronolactone has been shown to be convertible to L-ascorbic acid

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458 XYLITOL METABOLISM

(29-31). In these transformations there is no evidence for cleavage of the carbon chain (32-35). It is realized by the present authors that there may be a difference in mechanisms of biosynthesis of the glucuronate moiety of conjugated glucuronides and the glucuronate precursor of L-ascorbic acid. Nevertheless, drugs which stimulate conversion of n-glucose to L-ascorbic acid similarly influence the conversion of n-glucose to n-glucuro- nate (36). The transformation of glucose to glucuronate might occur via uridine diphosphate derivatives (37) or by way of myo-inositol, which has recently been shown to be converted to nn-glucuronate by a rat kidney preparation (33). The work of three groups of investigators (30,31,3942) indicates that L-gulonolactone (or L-gulonate)’ is an intermediate in the conversion of n-glucuronolactone (or n-glucuronate) to L-ascorbic acid. Isotopic studies by the present authors (2) are consistent with L-gulonate being an intermediate in the conversion of n-glucuronolactone to L-xylulose in the pentosuric human, and Bublitz, Grollman, and Lehninger (42) have found that, depending upon experimental conditions, rat liver extracts can convert L-gulonate to either L-ascorbic acid or L-xylulose. In addition, Ashwell (43) has prepared an enzyme system from an aqueous extract of rat liver acetone powder which can convert o-glucuronate (and n-galac- turonate) to a reaction product which is readily converted to L-xylulose by mild treatment with acid. These findings, together with enzymatic studies on xylitol and the xyluloses (3, 4, 7, 8) and with the tracer experi- ments reported in the present paper, can best be summarized by Dia- gram I, which includes enzymatic cofactors where they are known.

It is possible that 3-keto-L-gulonate is involved in the conversion of L-gulonate to L-xylulose or L-ascorbic acid (1, 42). Enolization and lac- tonization would yield the vitamin, while decarboxylation would lead to the pentose. These transformations cannot both be spontaneous reac- tions of enzymatically produced 3-keto-L-gulonate, since there seems to be a marked distinction between the metabolism of L-gulonate in the rat and in the guinea pig. Burns* and Evans (31) have shown that L-gulonolactone is rapidly oxidized to CO2 in both species (presumably via L-xylulose), but only in the rat is it converted to L-ascorbic acid. Hence, if a common intermediate exists between L-gulonate on one hand, and L-ascorbic acid and L-xylulose on the other, the disposition of the intermediate must be, at least in part, enzymatically determined. A number of possibilities can

1 It has not as yet been clearly established whether the forms in which n-glucuronic acid and L-gulonic acid react are the lactones or salts. Although in uivo experiments, such as those of Burns and Evans (31), indicate that only the lactones are metaboli- cally active, this does not hold for enzymatic studies (4143).

2 We wish to acknowledge discussions with Dr. John J. Burns in which there has been an exchange of current experimental results and of speculations regarding the interrelationship of our respective studies.

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D. B. MCCORMICK AND 0. TOUSTER 450

be postulated, but experimental evidence is required for their substantia- tion. It would appear that the oxidation of L-gulonate involves complex mechanisms, perhaps including the formation of 3-keto+gulonate stably linked to phosphate, coenzyme A, or an enzyme.

Certain drugs, such as Chloretone and barbital, apparently increase the rate at which glucose enters the proposed pathway, as determined by isolation of unconjugated urinary n-glucuronic acid (36), L-gulonic acid (44), and L-ascorbic acid (45). In fact, one drug, aminopyrine, stimulates L-ascorbic acid excretion in the rat (46) and L-xylulose excretion by pen- tosuric humans (47). Burns et al. have pointed out that the drug effects

I-CO HbOH

HC.O HCOH

H2FOH COOH “p-l

HOtH HCOH

HO&H TPNH HOtH HdH

i!3 HodH ---*

/

H+OH HtOH- H&OH %) HdOH ---* Ht HCOH HLOH HtOH HOCH

H2bOH tOOH HOiH

@OH H2bH H2bOH

D-GLUCOSE D-GLUCURONATE L- GULONATE ‘\ L-ASCORBIC ACID

HEXOSE-& \

PHoSPHATE

\ \ \

PENTOSE \

PHy’H&;eTE \ \

2

‘L H2FH H2COH

r ATP +

H2COH H,fOH H,tOH

DPN H&OH

HO,H b HOCH t- HOtH H°C,H TPNH $0

c, HCOH-HCOH HCOH HbH

H2tOqH2 H2iOH HtOH HOtH HO&H ,t H2OH H2tOH H2tOH

D-XYLULOSE-J- D-XYLULOSE XYLITOL L-XYLULOSE PHOSPHATE

DIAGRAM I

on the six carbon compounds are unrelated to any known detoxication mechanisms (36), and a similar observation has been made concerning L-xylulose excretion by pentosurics (1). Lastly, it should be noted that hypophysectomized rats show little response to barbital and Chloretone as far as L-ascorbic acid production is concerned (36).

There are no published data inconsistent with the formulation of the sequence of reactions shown in the diagram, and there is ample isotopic and enzymatic evidence in its favor. Additional physiological studies will be necessary to support the scheme and then to determine its value in species which cannot synthesize L-ascorbic acid. Furthermore, there may be additional side paths from the cycle. This is suggested by the recent finding of L-arabitol, perhaps derived from the reduction of L-xylulose, in the urine of a pentosuric human (48).

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460 XYLITOL METABOLISM

SUMMARY

The guinea pig converts xylitol-1-C” to respiratory C140z to an appreci- able extent, a portion of the polyol apparently being excreted as such in the urine. ~-Xylose-l-C~~ is oxidized to C”OI by the rat and the guinea pig; in the latter species, most of the administered radioactivity is excreted in the urine.

Xylitol is incorporated into liver glycogen at least as efficiently as is D-ribose, in both rat and guinea pig. With both xylitol and D-ribose, carbons 1 and 3 of the derived glucose contained most of the radioactivity, with carbon 1 having the greater activity. No significant differences in the pattern of labeling were observed between the rat and the guinea pig in the xylitol experiments.

The findings appear to confirm enzymatic experiments which indicate that xylitol is successively converted to D-xylulose, D-xylulose 5-phosphate, and other intermediates of the pentose phosphate shunt. Implications regarding a new pathway for the metabolism of glucose, involving its conversion to D-glucuronate, L-gulonate, and the enantiomorphic forms of xylulose, are discussed.

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Donald B. McCormick and Oscar TousterPENTOSE PHOSPHATE PATHWAYXYLITOL TO GLYCOGEN VIA THE

THE CONVERSION IN VIVO OF

1957, 229:451-461.J. Biol. Chem. 

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