LECTURE ON BIOLOGICAL CHEMISTRY FOR 2 YEAR STUDENTS

OF MEDICAL FACULTY ( 2005- 2006)

LECTURE 23
THEME: BIOCHEMISTRY OF THE LIVER AND KIDNEY URINE
FORMATION
!LAN OF LECTURE
" B#$%$&#'(% )*+',#$+- $) ,./ %#0/1
2 R$%/ $) ,./ %#0/1 #+ '(12$.341(,/ 5/,(2$%#-5.
3 R$%/ $) ,./ %#0/1 #+ %#6#4 5/,(2$%#-5
7 R$%/ $) ,./ %#0/1 #+ 61$,/#+ 5/,(2$%#-5
5 R$%/ $) ,./ %#0/1 #+ 4/,$8#)#'(,#$+ 61$'/--/-
6 B#$%$&#'(% )*+',#$+- $) ,./ 9#4+/3
: M/'.(+#-5 $) *1#+/ )$15(,#$+
; R/+(% 1/&*%(,#$+ $) (1,/1#(% 2%$$4 61/--*1/
< R/+(% 1/&*%(,#$+ $) ('#4 = 2(-/ 2(%(+'/
"0 !.3-#'(% (+4 './5#'(% '.(1(',/1#-,#'- $) *1#+/
B#$%$&#'(% F*+',#$+- $) ,./ L#0/1:
1. Metabolic Functions
Liver is a key organ and hence believed to be the principal site for the following
reactions :
(a) Conversion of absorbed monosaccharides e.g. galactose and fructose into
glucose.
(b) Cholesterol biosynthesis, its esterification and excretion.
(c) iosynthesis of plasma proteins e.g. albumin and globulins.
(d) Conversion of ammonia into urea.
2. Secretory Function
Liver is largely responsible for bile pigment metabolism by converting bilirubin,
formed from heme catabolism, into bilirubin diglucuronides and secreting them
through bile.
3. Detoxication and Protective Functions
Liver (!upffer cells) can remove foreign bodies from blood by phagocytosis. "t can
detoxify various drugs and hormones by converting them into less toxic substances
which are excreted.
4. Storage Functions
Liver stores glucose in the form of glycogen. "t is also responsible to some
extent for the storage of some vitamins e.g vitamin A and
#$
.
5. Syntesis o! "lood #oagulation Factors
%reprothrombin (inactive form) is converted into prothrombin in liver in the
presence of vitamin !. &ther coagulation factors e.g. factor ', '"" and ( are also
synthesi)ed in the liver.
$. %xcretory Functions
romosulphthalein (*%) and +ose engal dye are exclusively found to be
excreted through liver cells.
&. 'andling o! %n(ymes
,uch significance is attributed to liver for handling of en)ymes like alkaline
phosphatase (-L%) and release of transaminases e.g. aspartate transaminase (.&/)
and alanine transaminase (.%/).
). Miscellaneous Functions
(a) lood formation in embryo.
(b) lood formation in adults in some abnormal states.
R$%/ $) ,./ %#0/1 #+ '(12$.341(,/ 5/,(2$%#-5.
0rom intestine glucose pass into the liver, where most part of it undergoes the
phosphorylation. .lucose121phosphate is formed as result of this reaction, which is
cataly)ed by two en)ymes 3 hexokinase and glucokinase. 0ructose and galactose also
are transformed into glucose121phosphate in the liver.
.lucose121phosphate is a key product of carbohydrates metabolism. "n the liver
this substance can metaboli)ed into different ways depend of liver4s and whole
organism4s necessity.
#. *ynthesis of glycogen. Content in the liver 3 561#66g. -fter eating amount
of glycogen in the liver increase up to #76g. -fter $8 hours of starvation content of
glycogen in the liver decreases to )ero and glukoneogenesis started.
$. .lucose121phosphatase catali)e dephosphorylation of glucose121phosphate
and free glucose is formed. /his en)yme is present in the liver, kidney and small
intestine. /his process maintain normal level of glucose in the blood.
9. :xcess of glucose121phosphate, which is not used for the synthesis of
glycogen and formation of free glucose, is decomposed in glycolysis for pyruvate and
for acetyl1Co-, which are used for fatty acids synthesis.
8. .lucose121phosphate is decomposed for ;
$
& and C&
$
, and free energy for
hepatocytes is formed.
7. %art of glucose121phosphate is oxidi)ed in pentosophosphate cycle. /his way
of glucose decomposition supplyes reducted <-=%;, which is necessary in fatty
acid synthesis, cholesterol synthesis, and also pentosophosphates for nucleic acids.
<ear #>9 of glucose in liver is used for this pathway, another $>9 3 for glycolisis.
;epatocytes content full set of gluconeogenesis necessary en)ymes. *o, in
liver glucose can be formed from lactate, pyruvate, amino acids, glycerine.
.luconegenesis from lactate takes place during intensive muscular work. Lactate is
formed from glucose in muscles, transported to the liver, new glucose is formed and
transported to the muscles (!ori cycle).
R$%/ $) ,./ %#0/1 #+ %#6#4 5/,(2$%#-5
/he lipid content of liver is about 7?, but all processes of lipid metabolism
take place there. ,ost important of them are following:
#. Lipogenesis (synthesis of fatty acids and lipids). *ubstrate for this process 3
acetyl1Co-, formed from glucose and amino acids, which are not used for another
purposes. /his process is very active when the person eats a lot of carbohydrates.
Liver synthesi)es saturated and monounsaturated fatty acids more active than another
tissues. 0atty acids then are used for the synthesis of lipids, phospholipids,
cholesterol ethers. .lycerol191phosphate, which is necessary for lipids synthesis,is
formed in liver in result of two processes: from free glycerol under influence of
glycerolkinase, or in reducing of dioxiacetone phosphate under influence of
glycerolphosphate dehydrogenase. -ctive form of fatty acids interact with glycerol191
phosphate and phosphatidic acid is formed, which used for synthesis of
triacylglycerines and glycerophospholipids.
$. Liver play a central role in the synthesis of cholesterol, because near @6 ?
of its amount is synthesi)ed there. iosynthesis of cholesterol is regulated by
negative feedback. Ahen the level of cholesterol in the meal increases, synthesis in
liver decreases, and back to front. esides, synthesis is regulated by insulin and
glucagon. Cholesterol is used in the organism for building cell membranes, synthesis
of steroid hormones and vitamin =. :xcess of cholesterol leads out in the bile to the
intestine. -nother part of cholesterol is used for bile acids synthesis. /his process is
regulated by reabsorbed bile acids according to negative feedback principles.
9. Liver is a place of ketone bodies synthesis. /hese substances formed from
fatty acids after their oxidation, and from liver transported to another tissues, first of
all to the heart, muscles, kidneys and brain. /hese substances are main source of
energy for many tissues of our organism excepting liver in normal conditions (heart)
and during starvation (brain).
R$%/ $) ,./ %#0/1 #+ 61$,/#+ 5/,(2$%#-5.
Liver has full set of en)ymes, which are necessary for amino acids metabolism.
-mino acids from food are used in the liver for following pathways:
#. %rotein synthesis.
$. =ecomposition for the final products.
9. /ransformation to the carbohydrates and lipids.
8. "nteraction between amino acids.
7. /ransformation to the different substances with amino group.
2. +elease to the blood and transport to another organs and tissues.
/he high speed of protein synthesis and decomposition is typical for the liver.
;epatocytes catch different protein from blood (from hemolysated +C, denaturated
plasma proteins, protein and peptide hormones) and decompose them to the free
amino acids which are used for new synthesis. Ahen organism does not get necessary
Buantity of amino acids from food, liver synthesi)es only very necessary proteins
(en)ymes, receptors).
Liver synthesi)es about #66 ? of albumines, C6 ? of D
#
1globulines, 57 ? of
D
$
1globulines, 76 ? of E1globulines, blood clotting factors, fibrinogen, protein part of
blood lipoproteins, such en)yme as cholinesterase. /he speed of these processes is
enough high, for example, liver synthesi)es #$1#2g of albumines per day.
-mino acids, which are not used for protein synthesis, are transformed into
another substances. &xidative decomposition of amino acids is main source of energy
for liver in normal conditions.
Liver can synthesi)e non1essential amino acids.
Liver synthesi)es purine and pyrimidine nucleotides, hem, creatin, nicotinic
acid, cholin, carnitin, polyamines.
R$%/ $) ,./ %#0/1 #+ 4/,$8#)#'(,#$+ 61$'/--/-.
- xenobiotics is a compound that is foreign to the body. /he principal classes
of xenobiotics of medical relevance are drugs, chemical cancerogens, and various
compounds that have found their way into our environment by one route or another
(insecticides, herbicides, pesticides, food additions, cosmetics, domestic chemical
substances). ,ost of these compounds are subFect to metabolism (chemical
alteration) in the human body, with the liver being the main organ involvedG
occasionally a xenobiotics may be excreted unchanged.
*ome internal substances also have toxic properties (for example, bilirubin,
free ammonia, bioactive amines, products of amino acids decay in the intestine).
,oreover, all hormones and mediatores must be inactivated.
+eactions of detoxification take place in the liver. ig molecules like bilirubin
excreted with the bile to intestine and leaded out with feces. *mall molecules go to
the blood and excreted via kidney with urine.
/he metabolism of xenobiotics has $ phases:
I+ 6.(-/ ", the maFor reaction involved is hydroxylation, cataly)ed by
members of a class of en)ymes referred to as monooxygenases or cytochrome %1876
species. /hese en)ymes can also cataly)e deamination, dehalogenation, desulfuration,
epoxidation, peroxidation and reduction reaction. ;ydrolysis reactions and non1%1
8761cataly)ed reactions also occur in phase $.
I+ 6.(-/ 2, the hydroxylated or other compounds produced in phase # are
converted by specific en)ymes to various polar metabolites by conFugation with
glucuronic acid, sulfate, acetate, glutathione, or certain amino acids, or by
methylation.
/he overall purpose of metabolism of xenobiotics is to increase their water
solubility (polarity) and thus facilitate their excretion from the body via kidney.'ery
hydrophobic xenobiotics would persist in adipose tissue almost indefinitely if they
were not converted to more polar forms.
"n certain cases, phase # metabolic reaction convert xenobiotics from inactive
to biologically active compounds. "n these instances, the original xenobiotics are
referred to as prodrugs or procarcinogens. "n other cases, additional phase # reactions
convert the active compounds to less active or inactive forms prior to conFugation. "n
yet other cases, it is the conFugation reactions themselves that convert the active
product of phase # to less active or inactive species, which are subseBuently excreted
in the urine or bile. "n a very few cases, conFugation may actually increase the
biologic activity of a xenobiotics.
;ydroxylation is the chief reaction involved in phase #. /he responsible
en)ymes are called monooxygenases or cytochrome %1876 species. /he reaction
cataly)ed by a monooxygenase is:
RH + O
2
+ NADPH + H
+
R-OH + H
2
O + NADP
+; above can represent a very widee variety of drugs, carcinogens, pollutants,
and certain endogenous compounds, such as steroids and a number of other lipids.
Cytochrome %1876 is considered the most versatile biocatalyst known. /he
importance of this en)yme is due to the fact that approximately 76 ? of the drugs that
patients ingest are metaboli)ed by species of cytochrome %1876. /he following are
important points concerning cytochrome %1876 species:
#. Like hemoglobin, they are hemoproteins.
$. /hey are present in highest amount in the membranes of the endoplasmic
reticulum (:+) (microsomal fraction) of liver, where they can make up approximately
$6 ? of the total protein. /hay are also in other tissues. "n the adrenal, they are found
in mitochondria as well as in the :+G the various hydroxylases present in that organ
play an important role in cholesterol and steroid biosynthesis.
9. /here are at least 2 closely related species of cytochrome %1876 present in
liver :+, each with wide and somewhat overlapping substrate specificities, that act
on a wide variety of drugs, carcinogens, and other xenobiotics in addition to
endogenous compounds such as certain steroids.
8. <-=%;, not <-=%, is involved in the reaction mechanism of cytochrome
%1876. /he en)yme that uses <-=%; to yield the reduced cytochrome %1876 is
called <-=%;1cytochrome %1876 reductase.
7. Lipids are also components of the cytochrome %1876 system. /he preferred
lipid is phosphatidylcholine, which is the maFor lipid found in membranes of the :+.
2. ,ost species of cytochrome %1876 are inducible. 0or instance, the
administration of phenobarbital or of many other drugs causes a hypertrophy of the
smooth :+ and a 91 to 81fold increase in the amount of cytochrome %1876 within 817
days. "nduction of this en)yme has important clinical implications, since it is a
biochemical mechanism of drug interaction.
5. &ne species of cytochrome %1876 has its characteristic absorption peak not
at 876 nm but at 88@ nm. "t is often called cytochrome188@./his species appears to
be relatively specific for the metabolism of polycyclic aromatic hydrocarbons (%-;s)
and related moleculesG for this reason it is called aromatic hydrocarbon hydroxylase
(-;;). /his en)yme is important in the metabolism of %-;s and in carcinogenesis
produced by this agents.
@. +ecent findings have shown that individual species of cytochrome %1876
freBuently exist in polymorphic forms, some of which exhibit low catalytic activity.
/hese observation are one important explanation for the variations in drug responses
noted among many patients.
"n phase # reactions, xenobiotics are generally converted to more polar,
hydroxylated derivates. "n phase $ reactions, these derivates are conFugated with
molecules such as glucuronic acid, sulfate, or glutatione. /his renders them even
more water1soluble, and they are eventually excreted in the urine or bile.
/here are at least 7 types of phase $ reactions:
" G%*'*1$+#4(,#$+ H=%1glucuronic acid is the glucuronyl donor, and a
variety of glucuronyl transferases, present in both the :+ and cytosol, are the
catalysts. ,olecules such as bilirubin, thyroxin, $1acetylaminofluorene (a
carcinogen), aniline, ben)oic acid, meprobromate (a tranBuili)er), phenol, cre)ol,
indol and skatol, and many steroids are excreted as glucuronides. /he glucuronide
may be attached to oxygen, nitrogen, or sulfur groups of substrates. .lucuronidation
is probably the most freBuent conFugation reaction.
2 S*%)(,#$+ *ome alcohols, arylamines, and phenols are sulfated. /he sulfate
donor in these and other biologic sulfation reactions is adenosine 9I1phosphate17I1
phosphosulfate (%-%*)G this compound is called active sulfate.
3 C$+>*&(,#$+ ?#,. G%*,(,.#$+/ .lutathione (J1glutamylcysteinylglycine) is
a tripeptide consisting of glutamic acid, cysteine, and glycine. .lutathione is
commonly abbreviated to .*;G the *; indicates the sulfhydryl group of its cysteine
and is the business part of the molecule. - number of potentially toxic electrophilic
xenobiotics (such as certain carcinogens) are conFugated to the nucleophilic .*;.
/he en)ymes cataly)ing these reactions are called glutathione *1transferases and are
present in high amounts in liver cytosol and in lower amounts in other tissues.
glutathione conFugates are subFected to further metabolism before excretion. /he
glutamyl and glycinyl groups belonging to glutathione are removed by specific
en)ymes, and an acetyl group (donated by acetyl1Co-) is added to the amino group
of the remaining cystenyl moiety. /he resulting compound is a mercapturic acid, a
conFugate of L1acetylcysteine, which is then excreted in the urine.
8. A'/,3%(,#$+ /hese reactions is represented by @ A A'/,3%-C$A B A'/,3%-@
A C$A, where ( represents a xenobiotic. /hese reactions are cataly)ed by
acetyltransferases present in the cytosol of various tissues, particularly liver. /he
different aromatic amines, aromatic amino acids, such drug as isonia)id, used in the
treatment of tuberculosis, and sulfanylamides are subFects to acetylation.
%olymorphic types of acetyltransferases exist, resulting in individuals who are
classified as slow or fast acetylators, and influence the rate of clearance of drugs such
as isonia)id from blood. *low acetylators are more subFect to certain toxic effects of
isonia)id because the drug persists longer in these individuals.
7. M/,.3%(,#$+ - few xenobiotics (amines, phenol, tio1substances, inorganic
compounds of sulphur, selen, mercury, arsenic) are subFect to methylation by
methyltransferases, employing *1adenosylmethionine as methyl donor. -lso
catecholamines and nicotinic acid amid (active form of vitamin %%) are inactivated
due to methylation.
B#$%$&#'(% )*+',#$+- $) ,./ 9#4+/3
/he kidneys are paired organs, which are responsible for the constancy of the
internal environment in the organism and elimination of the metabolism end1
products./he kidneys regulate water1electrolyte balance, acid1base balance, excretion
of metabolic wastes, osmotic pressure. esides, they take part in the regulation of
blood pressure and +..C production
:ach kidney is composed of $ layers: the cortex or outer layer is brownish1 red
and the medulla or inner layer is lighter in colour. /he nephron is the functioning unit
of the kidney. :ach kidney contains more than a million of nephrons.
"t consists of renal corpuscle, which contains glomerulus surrounded by hollow
capsule (owman4s capsule). esides each nephron contains: proximal convoluted
tubules, a descending limb of the loop of ;enle, collecting tubules and distal
convoluted tubules.
/he $ principal types of nephron are classified according to their position in the
kidneys:
#. Cortical nephrons (@7?), which are situated in the cortex.
$. Kuxtamedullary nephrons (#7?)
/he kidneys are the main organs of the elimination. /hey take part in the
elimination of the end1products of proteins metabolism, water and salts. /he kidneys
are the most important organs of excretion. - human dies when the kidneys are not
functioning for 812 days.
/he kidneys4 tissue contains a lot of water (about @8? ). /he kidneys absorbe
approximately #6? of the oxygen, which is used by the organism.
5661C66 l of blood passes through the kidneys per day.
Carbohydrates are basic energetic materials for the work of kidneys.
!etolysis, glycolysis, aerobic oxidation and phosphorylation take place in the
kidneys. -erobic metabolism dominates in the cortex, and in medulla 1anaerobic.
%rotein metabolism is very intensive in kidneys. -s a result ammonia is formed from
glutamine and guanidineacetate from arginine and glycine. /hen guanidineacetate is
transformed in to creatine in the liver . /here are many en)ymes in the kidneys4
tissues :L=;, -s-/, -l-/. L=;
#
and L=;
$
dominate in the cortex and L=. 9,7 in
the medulla.
M/'.(+#-5 $) *1#+/ )$15(,#$+
0luid , which contains different organic and non1organic substances, and is
eliminated from the organism is urine. Hrine contains: water, metabolic wastes,
mineral salts, hormones, vitamins, and their derivates, toxins.
;ow urine is formedL
/here are 9 basic renal processes: filtration, reabsorption and secretion.
*lomerular !iltration is caused by difference between glomerular pressure (56 mm
;g), colloid oncotic pressure (96 mm ;g) and capsular pressure ($6 mm ;g).
/he effective filtration pressure is approximately 56mm;g 1 (96mm;g M
$6mm;g) N $6mm;g . &ncotic M capsular pressure must be lower than glomerular
pressure. -s a result of the filtration primary urine is formed. -ssuming that the
kidneys are healthy and filter approximately $6? of the plasma they receive each
minute, they will produce #@6 to $66 l of filtrate per day. /his fluid is essentially
protein1free and contains mostly crystalloids in the -ame concentrations as in the
plasma. -pproximately CC? of the filtrate must be returned to the vascular system,
while #? is excreted in the urine. /he return flow of filtered molecules from the
tubules to the blood is called reabsor+tion. *ome substances are not being
reabsorbedG such as: urea, uric acid, creatinine etc. /ubules reabsorb #5C l of water,
#kg of <aCl, 766g of <a;C&
9
, $76g of glucose, #66g of amino acids per day. "n
addition, some substances are secreted by tubular cells (bases, acids, drugs, etc.). -s a
result of the reabsorption, secondary urine is formed (#1$ l per day).
*ome of the blood that passes through the kidneys, in the other words, is OclearedP
from waste products.
"f a substance is neither reabsorbed nor secreted by the tubules, the amount of
excreted per minute in the urine will be eBual to the amount that is filtered out of the
glomeruli.
/he renal plasma clearence is the volume of plasma from which a substance is
completely removed in # minute by excretion in the urine.
+enal plasma clearence is calculated using formula:
C N 'QH
%
Ahere C1clearence
'1urine formation volume per minute (ml per min)
H1concentration of substance in urine (mg?)
%1concentration of substance in plasma (mg?)
0or example: clearence of inulin, creatinine is eBual to #$7 ml per min (because
they are not being reabsorbed)G /hese substances are used for the determination of
renal plasma clearence in medicine.
"f clearence R#$7, it means that substance is intensively secreted in tubules.
"f clearence S#$7, it means that there is some inflammatory process of the kidneys
(nephritis), which caused a)otemia.
/he biggest part of primary urine during its transference through kidney tubules
(the length of all kidney tubules is more than #66km) return many components into
blood. -pproximately all important for organism substances are reabsorbed. /he
mechanisms involved in this process may be divided into $ categories : simple
diffusion and active transport.
/he main portion of substances is reabsorbed by active transport which reBuires
the use of metabolic energy. /hat4s why system of active transport is very developed
in kidneys tubules. ;igh activity of <a
M
>!
M
-/%ase creates <a
M
>!
M
gradient for
secondary active transport of different substances. -ll the substances are divided into
9 groups due to their extent of reabsorption in proximal tubules :
#.*ubstances which are actively reabsorbed
$.*ubstances which are reabsorbed not enough
9.*ubstances which are not reabsorbed
"ons of sodium, chloride, magnesium, calcium, water, glucose and other
monosaccharides, amino acids, phosphates, hydrocarbonates, proteins, etc are
actively reabsorbed.
.lucose and proteins are reabsorbed approximately all, amino acids 1 up to C9?,
water 3 up to C2?, <aCl1 up to 56?, the other substances1 more than 76?.
+eabsorption of <a ions by the tubular epithelial cells is generally regarded as an
active transport. 0irstly <a ions pass from the kidney tubules into the epithelial cells
active transport. 0irstly <a ions pass from the kidney tubules into the epithelial cells
and from there1 into extracellular space.
/ubular reabsorption of Cl and ;C&
9
1
occurs passively in association with
reabsorption of <a
M
. Aater is absorbed isoosmotically with <a and also by flowing
along the osmotic gradient due to increase of osmotic pressure in extracellular space.
0rom there substances pass into capillaries.
.lucose and amino acids are transported by the special mediators in association
with <a. /hey use energy of <a
M
1 gradient on membrane Ca and ,g are reabsorbed
by the help of special -/%ase. %rotein is reabsorbed by endocytosis.
Hrea and uric acid belong to substances which are being reabsorbed not enough.
/hey are transported by simple diffusion into extracellular space, and from there1in
loop of ;enle.
Creatinine, mannitol, inulin 1 are substances which are not being reabsorbed.
0unctional significance of different parts of kidney tubules in the urine formation
is heterogeneous. =escending and ascending limbs of the loop of ;enle form the
countercurrent system which takes part in concentration and dilutation of the urine
due to the normal range for the specific gravity of urine which is from #.66$ to #.696.
LiBuid, which is transferred from the proximal tubule to descending limb of the
loop of ;enle, passes in kidney )one where concentration of osmoactive substances is
higher, than in cortex. /he walls of the ascending limb of the loop of ;enle are not
permeable to water. *alt (<aCl) is extruted into the surrounding tissue fluid. /he
descending limb does not actively transport salt. "t is however, permeable to water.
*ince the surrounding interstitial fluid is hypertonic to the filtrate in the descending
limb, water is drawn out of the descending limb by osmosis and enters blood
capillaries. /his system results in a gradually increasing concentration of renal tissue
fluid from the cortex to the inner medullaG the osmolality of tissue fluid increases
from 966m&sm>l to #876m&sm>l.
-scending limb of the loop of ;enle is responsible for reabsorption of Cl
1
and <a
M
ions, that4s why the fluid leaving the loop of ;enle is hypotonic. /he interstitial fluid
in this region (renal medulla) is correspondingly hypertonic.
+enal reabsorption of <a
M
and secretion of !
M
are regulated by aldosterone, the
principal mineralocorticoid secreted by the adrenal cortex. *ecretion of aldosterone is
increasing when concentration of <a
M
in blood is decreasing.
Ahen aldosterone is secreted in maximal amounts all of the sodium delivered to
the distal tubule is reabsorbed. Hnder these conditions, urine contains no <a
M
at all.
86126 l of water passes through the loop of ;enle per day. /hen this volume
decreases till $1#.7 l .
=ifferential reabsorption of water and dissolved substances takes place in the loop
of ;enle , distal tubules and collecting tubules by the help of $ mechanisms.
#. -ctive process in the loop of ;enle, which leads to appearance of high
osmolality in medulla and low osmolality in urine.
$. %assive process 1 due to secretion of antidiuretic hormone (-=;).
/his process guarantees reabsorption of water without dissolved compounds along
the osmotic gradient.
%rostaglandins influence for the elimination of water and <a
M
ions to. 0or example,
prostaglandins -
$
and :
$
stimulate diuresis and contribute to sodium excreation with
urine.
!
M
ions are reabsorbed in proximal tubules and exreted in distal tubules.
!
M
secretion is accompanied by reabsorption of <a
M
. /his occurs because the
aldosterone, that stimulated reabsorption of <a
M
,creates a large potential difference
between the $ sides of the tubular wall. /he secretion of !
M
into the tubular fluid is
driven by this electrical gradient. ecause of the <a>! exchange in the distal tubule,
an increase in <a reabsorption in the distal tubule results in an increase in !
M
secretion.
R/+(% 1/&*%(,#$+ $) (1,/1#(% 2%$$4 61/--*1/
/he kidneys are intimately involved in the regulation of arterial blood pressure.
+enin is secreted into the blood by the kidneys (Fuxtaglomerular apparatus).
&nce in the bloodstream, renin catalyses the splitting of a decapeptide, angiotensin ",
from a plasma protein known as angiotensinogen (alfa
$
1globulin), which is secreted
by the liver and is always present in the plasma in high concentration.
%lasma concentration of renin in patients with essential hypertension is increased.
"n healthy people renin in plasma is inhibited. Ae must say, that renin does not
influence on vessels.
%ressor activity has angiotensin "" which is formed from angiotensin " under the
influence of carboxycatepsin. -ngiotensin "" is a powerful vasoconstrictor which
causes appearance of hypertension.
-ll tissues, particularly the intestine and kidneys have high peptidase activity,
which destroys angiotensin "".
Tuxtaglomerular apparatus forms and excretes renin for the regulation of arterial
blood pressure (when it is increased).
-ngiotension "" stimulates the adrenal cortex to secrete aldosterone ,which
promotes the reabsorption of <aM in the distal convoluted tubules. ;ypertensive
activity of angiotension "" is regulated by plasma kinins ,which can cruse increasing
permeability of the capillaries and dilatation of the vessels ,which leads to
decreasing of blood pressure
radykinin and collydin are examples of such kinins./hese peptides are formed
from kininogen (plasma globulin)under the influence of trypsin, plasmin etc..
(kallikreins).
R/+(% 1/&*%(,#$+ $) ('#4 = 2(-/ 2(%(+'/
/he kidneys help to regulate the blood p;, together with respiratory system and
the blood buffer systems. lood buffer systems very Buickly react to violation of p;
(in 6.71# min)G lungs influence on hydrogen ions concentration in #19 min G and
kidney is the latest regulator of p; (in #61$6 hours). /here are $ main mechanisms
which are responsible for the kidneys regulation of blood p;: reabsorption of sodium
and secretion of hydrogen ions.
#) +eabsorption of sodium ions during transformation the alkaline phosphate
<a
$
;%&
8
of the blood to the acidic phosphate (<a;%&
8
) which is eliminated in the
urine.
$) Ahen the urine is acidic, ;C&
9
1
combines with ;
M
to form carbonic acid. Carbonic
acid in the filterate is then converted to C&
$
and ;
$
& by the action of carbonic
anhydrase. Carbonic acid dissociates to ;C&
9
1
and ;
M
. /hen ;
M
(acid) excreted in the
urine and ;C&
9
1
(base) passes in to the blood as <a;C&
9
and decreases the acidity.
9) -mmonia (<;
9
) is a base that is formed from the amino acid glutamine
within the tubular cells. "t crosses into tubular lumen to combine with ;
M
to form
ammonium (<;
8
). /his effectively prevents accumulation of ;
M
ions in the fluid, and
therefore permits continued exchange of ;
M
for <a
M
ions. /he amount of <a
M
ions
abbsorbed in the distal tubule is conseBuently reflected in the amount of both ;
M
and
<;
8
M
ions in the urine.
!.3-#'(% (+4 './5#'(% '.(1(',/1#-,#'- $) *1#+/
/he amount of urine (diuresis) excreated by a healthy man is #6661$666 ml per
$8 hours. =aily amount of urine, which is lower than 766 ml and higher than $666
ml, of adults is considered to be pathological. ,enUs diuresis is a little bit higher than
womenUs one, and it is #7661$666 ml, and womenUs diuresis is #6661#266 ml. /wenty
four hourUs diuresis can change depending on the kind of a diet, conditions of work,
the temperature of the environment and ets.
=rinking a lot of water causes the increase of diuresis to $66619666 ml, and
decrease of water drinking causes the decrease of diuresis to 566 ml and even less.
Consuming of fruits, berries and vegetables, rich in water also increase diuresis, but
dry products, especially salted, lower it. /he volume of urine is also lowered during a
work in hot shops when a man loses water mostly through sweating.
=iuresisUs increase (poliuria) is observed with many diseases and while using
different diuretics. - lot of urine is excreted by the patient who are ill with diabetes
mellitus and diabetes insipidus.
/wenty four hourUs decrease of urine excretion (oliguria) is observed while
having fever, diarhea, nausea, acute nephritis, heart deficieny and in some other
cases.
Ahen a man is lead or arsenic poisoned, is upset, has nephritis, the full stop of
urine excretion (anuria) is observed. %rolonged anuria causes uremia. -ccording to
standard, urine is discharged 918 times more by day 3 light time than at night. ut in
some pathological conditions (the beginning of heart decompensation, diabetes,
nephritis) become apparent by predominance of night discharge compare to day time.
*uch condition is called nicturia.
,rine-s colour. Hsually urine is straw 1yellow. "tUs main pigment is urochrome
which is formed from urobilin or urobilinogen during their interaction with some
peptides. *ome other pigments influence on the urineUs colour, thatUs uroerytryn which
is obviously derivate of melanin, uroporphyrins, riboflavin and others. =uring the
conservation obviously as a result of urobilinogen oxidation, urine darkens. *uch
urine is observed during bilirubinUs excretion when a man is ill with obstructive or
hepatic Faundice.
Concentrated urine, which is excreted in large Buantities and has high specific
gravity, is of bright1yellow color.
%ale urine has low specific gravity and is excreted in large Buantities.
Hrine can become of different colour shades when a patient has pathological
changes. Hrine is red or pink1red when a patient is ill with hematuria,
hemoglobinuria, when he takes amidopirin, santonin and other medicines. ;igh
concentration of urobilin and bilirubin can cause dark1red colour of urine..reen or
blue colour of urine is observed while albumin is rotting in the bowels and as a result,
indoxylsulphuric acids are produced. /he last ones while decomposing produce
indigo.
.rans+arency. 0resh urine is transparent. <ot fresh urine opacificates because of
mucins and the epithelium of the mucosal membrane of urethras. HrineUs
opacification is caused also by the crystals of oxalic acid (oxalates) and uric acid
(urates). =uring durable urine standing mostly urates are in fall1our, which,
adsorpting pigments, cause its opacification. Calcium and magnesium phosphates are
in fall1out in urine with alkaline reaction. -lkaline character of urine which is falling
out is caused by the decomposition of urea under the influence of urineUs microflora
to ammonia. -mmonia makes urine alkaline that causes the fall1out of mentioned
solts and urineUs darkening.
Hrine also becomes turbid when a patient is ill with inflamatory process of
urethra ducts while pus, proteins, blood cells falling into urine.
0or the diagnostics of some diseases urine is acidified and warmed up. "f after
this process cloudiness disappears it means that it is caused by calcium or magnesium
phosphates or urates. "f cloudiness doesnUt disappear it means that it is caused by
pus, epitheliym cells and by other admictures.
,rine/s s+eci!ic gravity depends on the concentration of dissolving substances.
=uring twenty four hours urineUs density changes from #.66$ to #.697 g >sm
9
which is
connected with periodical food and water intake and water output . 26127 grams of
hard substances are discharged with urine per day, specifically about $6 grams of
mineral left1overs. Hnder usually conditions an awerage level of urineUs density of
helthy person is #.6#$1#.6$6.
"ncrease of the density during a normal diuresis or poliuria is observed with that
patients who discharge a great amount of organic and nonorganic substanses. Hrine of
the person with diabetes mellitus contains sugar, ketone bodies and other
substances, which cause not only poliuria, but a high density ( to #.697). =aily
diureses with low specific density of urine is observed among the patients with
diabetes insipidus. Hrine with low density which is similar to primary urine (#.6#6) is
constantly discharged when a person has a complicated form of renal failure. *uch
condition is called sthenuria, and it speaks about the disturbance of the
concentrational functions of kidneys.
Low density of urine which have patients with diabetes incipidus (#.66#1#.668)
is the result of the disturbance of reverseble reabsorption of water in kidneyUs
canaliculi becouse of lack of antidiuretic hormone.
&liguria which accompanies acute nephritis is characteri)ed with high urineUs
density
,rine/s reaction. <ormally, having mixed food urine is acidic or light acidic
(p;N7.912.@). Hrine with p;N2 is usually taken as the norm. :ating mostly meat food
and proteins gives urine acidic reaction, while eating vegetables it become alkaline.
-cidic reaction of urine is mainly caused by onesubsubstituted phosphaties, mostly
<a;
$
%&
8
and !;
$
%&
8.
/wosubstituted phosphaties or biocarbonate potassium or
sodium predominate in alkaline urine. Considerable emimence of alkaline substances
in blood is accompanied with biocarbonates excretion with urine that raises p; from
2.6 to 5,715.5.
-lkaline reaction of urine is observed in patients who are ill with the cystitis
(inflammation of urinary bladder) which is connected with urea decomposition and
ammonia formation.
/he same reaction is observed after vomiting, drinking of alkaline mineral
waters and so on.
Clearly acidic reaction is notable for patients who are ill with diabetes mellitus,
during fever and starvation.
,rine/s smell. 0resh urine has a specific smell mainly caused by volatile acids
which are available in it. Hrine which is preserved, is influenced by microorganisms,
specifically by the decomposition of urea with ammonia forming. /he last one causes
acute ammonia smell. ;ealthy peopleUs urine can have different smell, depending on
kind of meals. ;aving some garlic, horseradish, onion gives urine specific smell.
/aking medicines and also some diseases can give urine specific smell to.
O1&(+#' '$56$+/+,- $) ,./ *1#+/
Proteins. ;ealthy man excretes about 96 mg of proteins with urine per day. /his
Buantity of the protein is not determined by ordinary lab. methods. -s a rule low
molecular proteins are eliminated , such as en)ymes( pepsin, trypsin , amilase,
ets.) , albumins. /he increasing of protein level in urine is called proteinuria.
/here are $ kinds of proteinuria: renal (real) and extrarenal (unreal or false).
+enal proteinuria is caused by organic demage of nephrons , due to blood proteins
(albumins and globulins) occur in urine. 0or example inflammation of glomeruluses
(glomerulonephritis )or nephrosis (violations of proteins reabsorption in tubules).
:xtrarenal proteinuria1 availability of proteins in urine due to diseases of urinary
tract. (inflammation of urinary bladder, urethritis). %atients with such diseases may
loose $6 186 g of protein with urine per day .
,rea is the main end1 product of the catabolism of amino acids and is the
substance in which is incorporated , for purposes of excretion, the bulk of the
nitrogen provided to the organism in excess of its needs. <itrogen of urea is eBual to
@6 1C6 ?of total nitrogen in urine.
-n adult eliminates $6197 g of urea with urine per day.
,ric acid:
-n adult eliminates 6.2 1 #g of uric acid with urine per day
#reatinine and #reatine:
-n adult excretes of #1$ g creatinine with urine per day. /he excretion of the
creatinine is constant from day to day and being determined chiefly by the muscle
mass. /he term Ocreatinine coefficientP is applied to the number of mg of creatinine
nitrogen excreted daily per kilogram of body weight. <ormal values are #@19$ for
men and #61$7 for women.
Amino Acids:
-n adult excretes about $19 g amino acids with urine per day. /wenty different
amino acids and their metabolites are determined in the urine. /he increasing of
amino acids concentration:
M#+/1(% '$56$+/+,- $) ,./ *1#+/
"n normal conditions daily urine contains #7 to $7 g of mineral components.
*odium chloride is the most wide1spread non1organic substance in urine. "t is
excreted in amounts ranging from @ to #2 g per day by the kidneys.
-bout # kg of sodium chloride passes through the glomeruluses every day and
only # ? of this Buantity is eliminated from the organism.
"n normal conditions daily urine contains $ to 7 g of potassium. %otassium and
sodium are excreted paired with an anion (for example #l
1
).
#alcium and magnesium:
"n normal conditions daily urine contains 6,#16,9 g of calcium. :xcreation calcium in
urine depends from its blood concentration. Ahen blood concentration of Ca is less
than @ mg ? calcium is not excreated in urine (for example hypoparathyroidism,
pregnancy).
"n normal conditions daily urine contains 6,6916,#@ g of magnesium.
*uch low #a and Mg concentration is because their salts are poorly soluble in
water.
0ron:
"n normal conditions daily urine contains about # mg of iron.
:xcessive breakdown of erythrocytes in hemolytic types of anemia causes the
increasing iron concentration.
Pos+orus:
%hosphorus is excreted in urine as !;
$
%&
8
or <a;
$
%&
8
.
Vuantity of excreted phosphate depends on blood p;:
#. -cidosis: -lkaline phophate (<a;
$
%&
8
) react with acids and are transformed
into acid phosphates(<a;%&8) which are eliminated in the urine.
$. -lkalosis: -cidic phosphates (<a;%&
8
) react with bases and are transformed
into alkaline phosphates (<a
$
;%&
8
) which are eliminated in the urine.
Sul+ur:
*ulphur is excreted in the urine as sulphates and paired compounds. "n normal
conditions daily urine contains $19 g of sulphur.
Ammonia:
/he ammonia which is present in the urine is formed in the kidneys from amino
acids , such as glutamine and asparagine, for purpose of neutrali)ation of excreted
acid.
Vuantity of ammonia salts is eBual to 912? of total urinary nitrogen. Hrinary
ammonia is increased in many conditions associated with acidosis( diabetes mellitus,
starvation , dehydration, etc.)
R/)/1/+'/-
#. Tohn A. *uttie. "ntroduction to iochemistry. 3 <ew Kork: ;olt, +inehart and
Ainston, "nc., #CC$.1 928 p.
$. Tohn ,c ,urry, ,ary :. Castellion. .eneral, &rganic and iological
Chemistry.1 <ew Tersy: %rentice ;all, #CC$.1 528 p.
9. +obert !. ,urray, =aryl !. .ranner. ;arper4s illustrated iochemistry. 3
"ndia: "nternational :ducation, $669.1 2C9 p.
%repared by "nna !rynytska
+evised
-dopted at the Chair *itting #5.62.67
,inutes W #$