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blood, and to become excreted in the urine.^

Eelative Metabolic Activity of the Tissues and Organs.

Before we trace the fate of the foodstuffs in the body, it is
important we should have an idea of the relative metabolic activity of
the tissues, since all essential changes which contribute to the pro-
duction of the energy of the body occur within the tissues.

It was at one time believed that the blood was the seat of
important oxidation processes ; but whilst it cannot be denied that a
certain amount of oxidation may occur in the blood, as shown by the
rapid diminution in the oxygen of the oxyhsemoglobin, on allowing blood
to stand in a closed vessel,^ it is certain that by far the greatest part of
the oxidations in the body occurs in the tissues, and especially in the
muscles. It was found by Pflliger, that frogs whose blood had been
wholly replaced by salt solution took in just as much oxygen, and gave
off just as much CO2, as normal animals.^ Moreover, Pembrey and
Glirber found hardly any alteration in the oxidation processes in rabbits
which had been deprived of a large proportion of their blood.'^

Placing the tissues in order of relative activity, the muscles must
take the first place ; next to these the secreting glands ; and next to
these the tissues of the nervous system, especially the grey matter.
Last in the scale come the skeletal tissues, which, performing as they
do a passive function, may be assumed to exhibit comparatively little
metabolic activity. With regard to the most active of the tissues,
namely, the muscles and the cells of secreting glands, we may note, in
passing, that their chemical composition is by no means identical.
The most prominent organic material in muscular tissue is native
proteid of the globulin class, whereas the most prominent organic
materials in the living tissue of gland cells are nucleo-proteids. This
distinction, though frequently ignored, is one of considerable import-
ance, for the nucleo-proteids have a constitution more complex than
that of proteids, consisting as they do of a combination of proteid with
phosphorus-containing substances, which yield as products of decomposi-
tion, xanthine bases, nucleins, paranucleins, and phosphoric acid, and
some of them, at all events, a carbohydrate (see pp. 66, 67).^

There can be very little doubt that the greater part of the oxidation
of the body occurs in the muscles. The formation of heat can, in fact,
be shown to be mainly due to the chemical activity of the muscles, an
activity called into play under the influence of the nervous system ;

^ Zillesen, Ztsclir. f. p^^ysiol. Chem., Strassbiirg, 1891, Bd. xv. S. 387; Araki, ibid.,
1891-4, Bde. xv., xvi., xvii., xix.

^ The disappearance of the oxygen of oxyhsemoglobin which occurs in blood on standing,
has been ascribed to the presence of hypothetical substances, to which the term "reducing
substances " has been applied. No chemical substances having such a reducing power have,
however, been either isolated from blood or chemically investigated. Moreover, the reduc-
tion of oxyhsemoglobin in blood on standing, may be due to its oxygen being removed
by the bioplasm both of the white corpuscles and of putrefactive bacteria, which rapidly
begin to appear and multiply in drawn blood. Reduction even occurs with solutions of
pure crystallized oxyhsemoglobin hermetically sealed in glass tubes.

^ Arch. f. d. ges. Physiol., Bonn, Bd. x. S. 251 ; see also CErtmann, ihid., 1877, Bd. xv.
S. 382.

■* Journ. Physiol., Cambridge and London, 1894, vol. xv. p. 449.

^ In connection with this question, the possibility must not be forgotten that even
ordinary proteids may have a carbohydrate nucleus in their molecule (cf. p. 64).



896 METABOLISM.

and the greater the amount of muscular activity the greater the amount
of oxidised materials in the form of carbonic acid and water that are
formed and got rid of from the body. It is probable that the oxidation
processes which occur in gland cells are by no means so active, for
although a gland when stimulated to activity receives a larger amount
of oxygenated blood, yet a considerable amount of the oxygen of that
blood simply passes through the capillaries without being absorbed, so
much so, in fact, that, as noted by Bernard, the blood of the veins of the
salivary glands during stimulation of their cranial nerves flows almost
as bright red as that of an artery. And in confirmation of this we find
that the largest gland in the body, the liver, is supplied with a relatively
small amount of arterial blood, and that almost the whole of its
metabolic activity is carried on with blood which already has passed
through the intestinal capillaries, and which has thereby been deprived
of a large part of its oxygen. Further, it was noted by Ludwig that the
saliva flowing from the duct of the submaxillary gland contains more
oxygen, than is dissolved in the plasma of the arterial blood, an
indication that the cells of the salivary glands cannot be greedy of
oxygen since they pass oxygen out along with the secretion rather than
retaining it for the formation of carbon dioxide and water. The
salivary glands, moreover, have been shown by the recent careful
observations of Bayliss and Hill ^ not to produce any appreciable amount
of heat ; and although it is stated that the blood flowing through the
liver is the warmest blood in the body,^ and warmer than that flowing
through the muscles, it must be borne in mind that it is almost
impossible to measure exactly the normal temperature of the blood
flowing from the muscles, because the operation necessary for observing
the temperature of such blood would tend to expose it to loss of heat.^

In conformity with, the conchision that the muscles are the organs which
possess by far the greatest amount of metabolic activity, it has been estimated
that the muscular tissues contain about one-fourth of the whole blood of the
body. The liver, which has important special functions to perform in
metabolism — functions which are, however, probably in large measure inde-
pendent of oxidation — contains another fourth of the blood, one-fourth is
employed in keeping full the larger arteries and veins, and all the rest of the
body put together has for its capillary supply only the remaining fourth. It
is clear, then, that in all observations and experiments upon the metabolism
of the body, the metabolism of the muscles must occupy a prominent place.

Nitrogenous Metabolism in the Tissues.

Of the proteids of the body Voit distinguishes two kinds — (1) Those
which form an integral part of the living substance or bioplasm, and (2)
those which occur in the tissue juice and in contact with the bioplasm,
but which are not to be regarded as forming an integral part of that
substance itself. To this latter kind he has given the name of " circu-

^ Journ. Physiol., Cambridge and London, 1894, vol. xvi. p. 351. Previously to this
work, it had been accepted, on the authority of Ludwig and otlrers, that the secretion of
saliva is accompanied by a marked production of lieat witliin tlie submaxillary gland.

" See p. 826. Waymouth Reid was unable to lind any eifect on the temperature of the
liver as the result of stinuUating the splanchnic and vagi nerves ("Proc. Phys. Soc,"
1895, p. xxxi., in Journ. Physiol., Cambridge and London, vol. xviii. ).

^ In his experiments upon the gaseous exchange in blood perfused through " surviving "
mammalian muscle, v. Frey found that the blood leaving the muscle was slightly warmer
than tha.t entering it {Arch. f. Physiol., Leipzig, 1885, p. 559).



NITROGENOUS METABOLISM IN THE TISSUES. 897

lating proteid," while the proteid which is assumed to actually form the
living substance of the tissues is termed by Voit, Organeiweiss, which
may be rendered in English by " organ- or tissue-proteid." ^ If the
term " circulating proteid " be used to include the proteids of the blood
and lymph as well as those which occur in the actual interstices, if
any, of the bioplasm, no exception can be taken to it, but if it
is used, as has been sometimes done by Voit, in a restricted sense,
merely to indicate proteid material which is interpolated amongst the
molecules of the proteid forming the bioplasm, without itself actually con-
stituting part of that substance, it must be admitted with Pfliiger ^ that
such employment of the term can only be misleading. Using, however,
the term circulating or unorganised proteid in the wider sense, there are
still two possibilities open as to the manner in which the proteids of the
body undergo metabolic changes — (1) We may assume that the circu-
lating proteid, reaching the tissues and becoming imbibed by them,
must be completely incorporated and built up into them' before it is
split up and oxidised ; or (2) it is open to us to suppose that the
unorganised proteid may be split up and oxidised outside the actual
molecules of the organised proteid of the living substance, but as a
consequence of the action of that substance. In the one case we may
suppose it to produce a direct formation or building up of bioplasm — a
transformation, in fact, of unorganised into organised proteid ; in the
other case, as undergoing contact changes by the action of the bioplasm,
much in the same way as contact changes are brought about by organised
ferments.

One reason for believing that the circulating proteid only becomes
in part built up into the material of the bioplasm, is derived from the
following observation (Voit). If, to an animal kept upon a diet con-
sisting of non-proteid food (fat), gelatin is given in an amount sufficient
to replace a caloric equivalent of such non-proteid material, it is found
that, reckoning for the amount of nitrogen due to the metabolised
gelatin, which always appears in full as urea, there is less nitrogen given
off from the, body than before ; that is to say, there is less tissue substance
broken down. But in the total absence of nitrogenous food there is a
definite amount of body proteid metabolised ; and since, when gelatin
is given, it is metabolised instead of part of this proteid, although it
cannot itself be built up into tissue substance (p. 878), it must be
assumed that the gelatin has taken the place of proteid which, although
in such intimate contact with the bioplasm as to become metabolised
under its influence, did not actually form bioplasm. It may further
be argued that the rapidity with which metabolic changes in proteids
occur within the body, and the large amount of such metabolism, when
excess of proteid is taken as food, render it improbable that all meta-
morphosed proteid has been built up to form bioplasm.

1 C. Voit, "Die Ernahning," Hermann's "Handbuch," Bd. vi. S. 301. The terms
"organised" and "unorganised" proteid are preferable to "tissue-" and "circulating-"
proteid, Avhicli have been used at different times in different senses. In earlier publications
{Ztschr.f. Biol., Mlinchen, 1874, Bd. x. ) Voit included the proteids of blood plasma under
the designation "Orgaireiweiss," founding this view upon the fact that, as the experiments
of Tschiriew {Bcr. d. k. sachs. Gesellsch. d. Wissenscli. , 1874, S. 411) and Forster (<S'ife?mg's6.
d. k.-hayer. Akad. d. Wissensch. zu Miinchen, 1875, S. 206) seemed to show, transfusion
of blood does not increase the proteid metabolism of the body. Pfliiger, however (loc. cit.,
iiif7'a, pp. 362 et seq.) has shown that the results of Tschiriew and Forster are capable of
a diametrically opposite interpretation.

2 Arch./, d. ges. Physiol., Bonn, 1893, Bd. liv. S. 333.

VOL. I.— 57



898 METABOLISM.

Yoit has drawn a much sharper distinction between the organised and
unorganised (tissue and circulating) proteid than that above indicated. He
denies that tissue proteid can as such undergo metabolism, even in inanition.
According to his view, it must first be dissolved up and take the form of
circulating proteid, and be carried in this form to other tissues {e.g. from the
muscles to the heart and nervous system), to be metabolised as circulating
proteid in these.^ This view is, however, difficult to reconcile with the
supposition that there is no chemical difference between the two forms of
proteid,- for if there is no such difference, it is not clear why the proteid
should not become metabolised in the tissues themselves, but should need to
be conveyed outside them before undergoing metabolic changes. Moreover, it
is entirely inconsistent Avith the experiments of Oertmann and Pflliger, of
Pembrey and Giirber, and of Schondorflf (with Pfliiger), which will be subse-
quently referred to.

The arguments and experiments by which Voit has endeavoured to support
his position are, however, quite insufficient to carry conviction, and it must be
regarded as having been rendered completely untenable by the experiments
and criticisms of Pfliiger.^ A view exactly the contrary to that of Voit was
taken by Liebig, and has been maintained by Hoppe-Seyler, and in a some-
what qualified form by Pfliiger. According to this view, it is only organised
proteid which can undergo metabolic changes — never unorganised. Unorgan-
ised proteid must therefore first be converted into organised before it is
capable of metabolism ; in other words, tissue bioialasm must be built uj) out of
circulating proteids before these last, which then of course have become
tissue proteids, can be broken down and oxidised. It is therefore denied that
any metabolism of proteids can occur outside the actual molecules of the living
substance — that, in short, there can be any contact action. It has, however,
been shown in the case of yeast, that chemical action may take place outside
the living cells, although under their direct agency, so that the possibility of
metabolic changes occurring under the influence of, but outside, the actual
molecules of the protoplasm of cells cannot be denied. Moreover, it is not
probable that the non-proteid materials (fat, carbohydrate, gelatin) of the
food become after assimilation built up into bioplasm, and although they are
undoubtedly taken into cell protoplasm they can hardly be regarded as
forming constituent parts of the molecules of its bioplasm. In this sense,
therefore, they are outside, although in contact with, the bioplasm of the
tissues ; nevertheless they are found to undergo metabolic changes under the
infliTence of that substance. It may, of course, be argued that they also are
really built up into the living proteid molecule, and must be so before they
can become metabolised, but there is absolutely no evidence that this is the
case, or that fat or carbohydrate are necessary constituents of bioplasm.

The fat drops which we see embedded in the protoplasm of cells, are
certainly not constituent parts of the bioplasm, although under its influence
they undergo physical and chemical changes, and the same is the case with
the glycogen clumps which can be seen in the liver cells, to say nothing of
the starch, aleuron, and fat granules of vegetable cells. The phenomenon of
contact change is in short too universal to be denied. Since this is so, the
most reasonable view to be taken of the matter appears to be one which
supposes that metabolism may occur both as a splitting-up and oxidation of
the molecules of living tissue or bioplasm, and as a splitting-up and oxidation

1 Loc. ciL, S. 303.

2 " Ich will also nicht daniit eiiien chemischen Unterscliied bezeichuen, soiidern
zunachst nur einen Unterschied in dem Orte an dem es sich befindet. . . . Ein und dassclbe
MolekUl Eiweiss kann in einem bestimmten Momente Eiweiss des Bhitplasnias, in einem
nachsten Eiweiss der Ernabrungsflussigkeit, in einem anderen Eiweiss der Lyniphe oder
auch Organeiweiss sein " {loc. ciL, S. 301).

'•' Loc. cit.



NITROGENOUS METABOLISM IN THE TISSUES 899

both of unorganised proteid and of non-proteid materials outside but in
contact with the molecules of bioplasm. Such a view, which is in a sense
intermediate between the extreme opinions advocated by Voit and Pfliiger
respectively, is consistent with all the known facts, and is more readily applic-
able to the phenomena, both of animal and vegetable metabolism, than the
exclusive acceptance of either of those opinions.

Whether directly or indirectly, tissue proteid normally undergoes meta-
bolism to the extent of about 1 per cent, of its substance per diem (Voit).

The proteids of the food are converted by digestion into albumoses
and peptones ; ultimately, probably, entirely into peptones. They are,
however, not absorbed as peptones, for no peptones are found in the
blood or chyle leaving the intestines. It is clear, therefore, that the
process of assimilation or the reconversion of peptones into proteids
must occur during their absorption, that is to say, in the substance of
the mucous membrane. It must not be forgotten, however, that a
certain amount of the proteid of food may possibly, as occurs in vitro,
be broken down beyond the stage of peptone into simpler nitrogenous
bodies, such as the amido-acids; and these, if their formation really
occurs to any extent in the intestinal tract, would be absorbed as such
into the portal blood and conveyed by it to the liver. Now we know
that the addition of amido-acids to the blood which is allowed to circu-
late through the liver, as well as their administration with the
food, causes an increase in the amount of urea in the blood after it has
passed through that organ, and an increased excretion of urea by
the kidneys.^ From this it may be assumed that any amido-acids
absorbed are converted by a process of synthesis (possibly preceded by
a previous more complete breaking-down, into ammonia compounds) into
urea. If this process of formation of amido-acids occurs at all in natural
digestion, it is obviously a change by which the proteids of the food
would not be directly serviceable for the production of tissue ; and in
this sense such conversion of peptones into amido-acids may be looked
upon as a direct waste of proteid food. It is extremely improbable that
such a change occurs to any extent in the normal organism, nor has the
presence of these substances to any marked degree been determined in
the normal intestinal contents. Moreover, as Bunge remarks, there
is not sufficient carbon in the proteid molecule to permit of all the
nitrogen issuing as amido-acids.'^ In any case, these bodies must
probably be split up and oxidised into carbon dioxide and ammonia, and
from these urea become formed by synthesis in the liver. We may
therefore probably put aside as exceptional this mode of transformation
of proteid into urea, and consider only the change which is undergone
by the proteid which is actually assimilated.

With regard to the agents in the mucous membrane which produce the
assimilation of proteids, that is to say the conversion of peptones into proteids,
there can be very little doubt that the columnar epithelium occupies the first
place. It is, however, difficult to prove that the change, which is one of
synthesis and dehydration, does actually occur in these cells. We have chiefly
analogy to guide us in coming to this conclusion. It can be definitely proved
that a synthesis of fat does occur in them ; and it is therefore probable that

1 Scliultzen and Nencki, Ztsckr. f. Biol., Milnclien, 1872, Bd. viii. S. 124 ; Salkowski,
Ztschr. f. physiol. Chem., Strassburg, 1879, Bd. iv. S. 100 ; v. Knieriem, Ztsclir, f. Biol.^
Mlinchen, 1874, Bd. x. S. 279.

" " Lectures," p. 320.



900 METABOLISM.

other syntheses which accompany assimilation, such as the formation of
proteids from peptones, must also' occur within them. Hofmeister ^ has
suggested that the leucocytes may also take an important part in determining
the assimilation of the foodstuffs. They are present in great abundance in
the intestinal mucous membrane, and especially those parts of that membrane
where absorption proceeds most extensively ; and they are also, it has been
shown, greatly increased in number during the process of absorption. It is,
however, difficult to obtain affirmative evidence upon this point, and since
leucocytes elsewhere do not possess this poAver, it is improbable that they are
the agents for such conversion in the intestine.

After assimilation the proteids are absorbed by the blood vessels of
the intestinal mucous membrane. The evidence for this has been
already given in the article on " Digestion and Absorption " (p. 433).
If any proteids are taken up by the lacteals of the small intestine, they
do not get into the thoracic duct,^ but must be transferred to the blood
vessels in passing through the mesenteric glands. At any rate we may
assume that nearly the whole of the proteids are ultimately taken by the
portal vein to the liver. The portal vein, therefore, contains the absorbed
material derived from digestion and assimilation of proteid food; it
must have, therefore (besides the ordinary constituents of blood plasma),
an additional amount of serum albumin or of serum globuhn, obtained by
the transformation of the peptones into these materials ; also extractives
of the meat or other forms of proteid diet (which are absorbed equally
by the blood vessels of the intestine), and in addition any products
of further decomposition of peptones, such as the amido-acids, the
possibility of the presence of which we have already discussed. But it
must be borne in mind that the blood flow through the portal system is
so large and rapid, that one could hardly expect these substances to be
absorbed into it in such a proportion that it would be possible to detect
by chemical means any appreciable difference of composition between
the blood of the portal vein and that of the system generally, nor are
there any satisfactory analyses directly showing such difference. ISTever-
theless there is a distinct physiological difference between the portal
blood collected during absorption of food, and especially of proteid food,
and the same blood collected during the intervals of digestion ; for it has
been shown that in the former case such blood, on being passed through
the liver, shows an increased amount of urea, whereas in the latter case
such an increase is not noticed. It is certain, at any rate, that the
products of absorption and assimilation of proteid foods are carried
to the liver, and, having traced them to this organ, we have next to
consider — (1) Whether they are stored at all within it; (2) whether
they undergo any change in passing through it.

Influence of the liver on proteid metabolism.— With regard to the
possible storage of proteid in the hver, it is open to us to suppose
that an excess of proteid material which is present in the portal blood
as the result of the absorption of proteid food, might be temporarily
taken up, at least in some measure, by the hepatic cells, and, after being

^ Arch. f. exper. Path. u. Pharmakol., Leipzig, 1884-7, Bde. xix. S. 1 ; xx. S. 29 ; xxii.
S. 306.

- Aslier and Barbera found, however, in a dog a marked rise both in the amount of
chyle and of the nitrogen of the chyle (estimated by Kjeldahl's method) during digestion
of purely proteid food, given by a gastric fistula. The rise was greatest at the sixth hour
after feeding, but there was a primary culmination at the second hour [CcntralU. f.
Physiol., Leipzig u. Wien, 1897, Bd. xi. S. 403).



INFLUENCE OF LIVER ON PROTEID MET/IBOLISM. 901

stored within them for a time, passed on into the hepatic blood to reach
the general circulation. There is, however, no clear evidence that such
storage takes place in the liver, or that if it does the stored proteid
undergoes any change within the liver cells.

When we examine the secretion of the liver, we find that it contains
a considerable amount of nitrogenous organic material (bile salts), in-
cluding a certain amount of sulphur in organic combination (taurine).
These nitrogenous and sulphur-containing materials can only be derived
from proteids, and since they are formed in greater amount during absorp-
tion of digested products than at other times, it might well be supposed
that they may be formed, at least in part, from the absorbed products
of proteid digestion. As against this conjecture, we cannot, however,
fail to notice that the appearance of these nitrogenous and sulphur-
containing materials in the bile salts is accompanied by a considerable
amount of material in the form of bile pigments, which can only be
derived from the haemoglobin of the red blood corpuscles; and since
haemoglobin readily decomposes into htematin, which is probably the
part directly converted, with elimination of iron, into bile pigment, and



Online LibraryE. A. (Edward Albert) Sharpey-SchäferText-book of physiology; (Volume v.1) → online text (page 125 of 147)