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v Steps between Coproporphyrinogen III (tetramethyl, tetrapropionic) and

protoporphyrin IX (tetramethyl, divinyl, dipropionic acid) are obscure. An oxidative decarboxylase system containing flavins as coenzvme, (probably the enzyme system consists of more than one enzyme,) converts Coproporphyrinogen III to protoporphyrinogen IX.

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v Protoporphyrinogen IX is converted to protoporphyrin IX by another

oxidase enzyme.

v The above steps require the presence of molecular O2.

Formation of Heme and Hemoproteins (Intramitochondrial): v Insertion of an atom of Fe++

into central position of protoporphyrin IX is catalyzed by heme syiithetnse (ferrochelrttase) which for optimal function requires

§ Anaerobiosis, and

§ Reducing agents such as glutathione

v The "heme" which is produced is then coupled to various proteins and

thus form the conjugated proteins, viz. hemoglobin, myoglobin, cytochrome C, catalases and peroxidases.

v This pathway operates inside mitochondrion

Catabolism of heme

The catabolism of hemoglobin is outlined in the graphic on the left. Red blood cells are continuously undergoing a hemolysis (breaking apart) process. The average life-time of a red blood cell is 120 days. As the red blood cells

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disintegrate, the hemoglobin is degraded or broken into globin, the protein part, iron (conserved for latter use), and heme (see middle graphic).

The heme initially breaks apart into biliverdin, a green pigment which is rapidly reduced to bilirubin, an orange-yellow pigment (see bottom graphic). These processes all occur in the reticuloendothelial cells of the liver, spleen, and bone marrow. The bilirubin is then transported to the liver where it reacts with a solubilizing sugar called glucuronic acid. This more soluble form of bilirubin (conjugated) is excreted into the bile.

The bile goes through the gall bladder into the intestines where the bilirubin is changed into a variety of pigments. The most important ones are stercobilin, which is excreted in the feces, and urobilinogen, which is reabsorbed back into the blood. The blood transports the urobilinogen back to the liver where it is either re-excreted into the bile or into the blood for transport to the kidneys. Urobilinogen is finally excreted as a normal component of the urine.

The destruction of RBC occur in reticulo endothelial cells

The reticulo endothelial system

Also known as the "mononuclear phagocyte system" the RES is composed of monocytes, macrophages, and their precursor cells. Monocytes

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arise from progenitor cellsin the bone marrow and are released into the blood. After migration to different tissues, they differentiate into macrophages with characteristic morphologic and functional qualities. Although RE cells residing in various tissues likely have different or highly specialized functions (e.g., immunoregulation, antimicrobial activity, antitumoricalactivity), one common task involves the clearance of particulatematter and damaged or effete cells.

The removal of damaged orsenescent erythrocytes, with the subsequent recycling of iron,directly links the RES and iron metabolism. This process is mainly carried out by RE cells of the spleen, liver, and bone marrow. The splenic red pulp appears to be one of the most active sites of red cell destruction. However, after splenectomy, macrophages of the liver and bone marrow (or elsewhere)can rapidly compensate for this function of the spleen.

Iron metabolism in the RES

Macrophages of the RES acquire most of their iron by phagocytosing senescent red blood cells. With each red cell ingested, themacrophage accrues approximately one billion iron atoms. After erythrophagocytosis, hydrolytic enzymes present in the phagolysosomedegrade the red blood cell. Proteolytic digestion of hemoglobin liberates heme, which is assumed to cross the phagolysosomalmembrane either by diffusion or by a specific transporter in order to reach heme oxygenase.).

www.ayurvedicmedicinalplants.com Receptor mediated uptake of hemoglobin

From kinetic studies of hemoglobin turnover in humans, it has been calculated that 10 to 20% of normal erythrocyte destruction occurs intravascularly, resulting in the release of hemoglobin. Under normal circumstances, all ofthis hemoglobin is rapidly bound by haptoglobin, which is thencleared from the circulation by parenchymal cells of the liver.Found in the highest concentrations in the spleen and the liver, CD163 scavenges hemoglobin by mediating endocytosis and subsequent degradation of the hemoglobin-haptoglobin complex.

Thus, uptake of hemoglobin-haptoglobin via CD163 may represent a significant pathway of normal iron acquisition by the RES.Under conditions associated with increased intravascular hemolysis (e.g., hemolytic anemia, thalassemia, and certain bacterialinfections), the hemoglobin-binding capacity of haptoglobin can be exceeded such that free hemoglobin appears in the plasma.Some of the circulating free hemoglobin degrades and releasesheme, which then becomes bound to the plasma glycoprotein hemopexin.

Specific hemopexin receptors on hepatocytes clear the heme- hemopexin complex from the circulation The detection of hemopexin receptors on human monocytic cell lines;also suggests that the RESis able to

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acquire heme from this pathway, but the amount taken up is probably not significant under normal circumstances.

Iron storage

The main sites of body iron stores are the hepatic parenchymaand the RES, particularly the RE cells of the bone marrow, spleen,and liver. The liver and the total bone marrow each contain approximately 100 to 300 mg of storage iron in healthy individuals. The concentrations of iron in liver and bone marrow have been shownto correlate well over a wide range (up to 9000 µg/g tissue) Iron in the RES most likely accumulates secondary to the catabolismof red cell heme.

RE iron acquired via erythrophagocytosis thatis not utilized or released is first destined for storage in ferritin, a cytosolic protein comprised of 24 subunits of twotypes, H and L. In RE cells, ferritin is comprised mainly ofthe L-subunit the form most associated with iron storage. Although ferritin synthesis after red cell ingestion can be regulated via IRP-IRE interactions effected by changes in iron levels, some evidence indicates that reactive oxygen species formed during phagocytosis may also play a role perhaps through upregulationof ferritin transcription.

The storage of iron from the uptake of hemoglobin appears to be influenced by genetic polymorphisms in haptoglobin. Of thethree haptoglobin

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polymorphisms in humans the multimeric Hp2-2 phenotype has the highest functional affinity for the hemoglobin scavenger receptor, CD163. Hemoglobin iron acquired via CD163 on RE cells is shunted into slowly exchanging storage compartments normally bypassed by iron recycling pathways

As the amount of iron in the cell increases, a larger percentagedeposits in hemosiderin, an insoluble, aggregated form of partiallydigested ferritin. Diversion of excess iron into hemosiderinpermits storage of more iron per unit volume in the cell, and,in fact, the highest concentrations of hemosiderin in the bodyare found in the RES

Iron release and plasma iron

Normal adult human plasma contains about 3 to 4 mg of iron, essentially all bound to transferrin. About 80% of the circulatingiron is en route between the RES and the bone marrow. Smallamounts of plasma iron are contributed by hepatic iron storesand by the absorption of dietary iron from the duodenum, but most circulating iron is contributed by the RES through the release of iron from catabolized senescent red cells Cyclic fluctuations in RE iron release appear to cause the pronounced circadian variation in plasma iron concentrations

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Marrow iron requirements appear to be an important factor in the physiological regulation of iron release from the RES. Whenbody (marrow) requirements increase, as in iron deficiency or venesection, iron release increases. Conversely, decreased marrow requirementsresulting from either hypertransfusion or bone marrow aplasia are associatedwith decreased iron release

From this it can be assumed that iron, porphyrins, factors influencing erythropoiesis all come under the heading of ranjaka pitta. The factors that contribute to the formation of other blood cells and their relative mechanisms could be classified under the heading of rakta dhatvagni. Rakta sarata occur when blood formed in a person is in its purest form and is some what related to hereditary.

Pitta is related to rakta, but only relationship with rbc s are evident. It is very difficult to pin point a factor comparable to ranjakapitta or rakta dhatwagni. At the end it is assumed that both of these are a group of substances taking part in the formation of blood cells.

When both are in normal condition production and coloration of blood will be normal which can also be clinically assessed by the assessment of hemoglobin and other blood parameters.

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We have seen that ranjaka pitta is a moiety of pitta with special function of controlling colouring factors in blood. Integrity of this pitta is assessed from the quantity and quality of blood. Doshas when they are normal are reflected from their functions. Regular functions of ranjaka pitta can be assessed from quality and quantity of blood (rakta).Qualitative analysis was done at that period was by physical appearance. There are a variety of signs available in our literature to propose pure blood.

Characteristics of pure blood

Pure rakta appear as bright red in colour, brightness is compared with that of indragopa (thrombidum) or like gold and normal colour is like padma (lotus flower), or alaktaka (lack) or gunjaphala (1)

The visuddha rakta purusha i.e. the person who possess pure rakta usually have the following qualities. –

Ø Attractive complexion

Ø Perfect functioning of sense organs

Ø Excellent digestive power

Ø Proper elimination of the waste products

Factors influencing Ranjaka Pitta

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Ø Healthy and happy

Ø Good strength and immunity

The rakta sara pareeksha provides information about the excellence of rakta dhatu. When blood become vitiated by doshas its colour, consistency etc will be changed. Quantitative increase of blood is assessed by skin diseases such as visarpa, kushta, upakusa, vyanga, and other symptoms such as spleen enlargement, giddiness, decreased digestion and other disorders of blood (2) A decrease in quantity of blood can be assessed by the desire to take food having sour taste, rather cold, less integrity in vessels and roughness to skin(3) .

There are varieties of factors which have an influence in the functioning of ranjaka pitta. It is subjective to food, environment, heredity, doshas, dhatus etc. we shall have an apparent view over such factors.

a. Role of food

According to Ayurveda food must have all six rasas and such food is capable of developing all dhatus. Chakrapani identifies the quantity of different food as one kudava of anna, two palas of mamsa, one pala of supa etc.Since rakta and ranjaka pitta have agneya guna, food which is agneya in nature must increase rakta and ranjaka pitta.

Agneya dravyas possess ruksha (dry), tikshna (sharp), ushna (hot), visada (clear), sukshma (subtle) and chiefly consist roopa guna (colour/vision).

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When consumed it creates daha (burning sensation), prabha (lusture), varna (colour), prakasa (bright) and helps in pachana (digestion)(4).

From the qualities attributed to agneya by Acharya,we can assume that hot, coloured vegetables and meat can increase ranjaka pitta and rakta.