Sub-chronic Effect Of Co-administration Of Methformine And Amilodipine On Some Haematological Indices In Experimental Animal
[A CASE STUDY OF WISTAR RATS]

This creates a problem for people who adhere to a strict vegetarian diet and supplementation via intramuscular injection and/or oral supplements may be required (Srinivasan et al., 2006). Certain algae and seaweeds have been proposed as sources of Vitamin B12 however the bioavailability of the vitamin from these sources is still disputed (Kwak et al., 2012). In a α-axial ligand corrin ring western country the average non-vegetarian diet includes around 5 to 8 micrograms of cobalamin daily. This is higher than the recommended daily allowance of 2.4 micrograms for adults, although this is higher in pregnant or lactating women (2.6 and 2.8 micrograms respectively) (Ou et al., 2006). A strict vegetarian however may consume only 0.5 micrograms a day and therefore be at the risk of deficiency. Due to our large natural stores of the vitamin it may take an extended period of time for a deficiency to develop however. The mode of absorption, trafficking and metabolic exchange that take place with Vitamin B12 highlight the rarity and essential nature of the compound (Gueant and Alpers, 2013).
Although the compound is seen to be carefully monitored throughout its metabolic pathway through the body system, it has been identified as being involved in only two important metabolic processes in the human body. These include the metabolism of Homocysteine (Hcy) and Methylmalonyl-CoA (MMA) (Srinivasan et al., 2006). In a broader sense, B12 is involved in the formation of red blood cells, to sustain function in the nervous system, DNA synthesis and cell proliferation (Ou et al., 2006). The journey of Vitamin B12 from intake to absorption follows the binding of the compound to several different protein structures and the involvement of numerous digestive enzymes (Ou et al., 2006). Vitamin B12 initially binds to haptocorrin following proteolytic digestion by pepsin in the low pH environment of the stomach (Gherasim et al., 2013). Haptocorrin are Vitamin B12 binding proteins that are produced in the salivary glands; however the actual binding does not occur until pepsin frees the vitamin from the proteins in the food (McGovern et al., 2008). The Vitamin B12-haptocorrin complex is referred to as “holo-R-protein” which remains bound until degradation by pancreatic proteases released into the upper small bowel (Srinivasan et al., 2006; Gherasim et al., 2013).
This allows the Vitamin B12 to be bound to gastric intrinsic factor (GIF), forming cobalamin-IF. This new complex travels to the distal ileum where recognition of its receptor which are selective for cobalamin-IF and not holo-R-protein allows the uptake of the vitamin complex (Alpers and Russell-Jones, 2013). The receptors are located on the enterocytes in the ileum thus uptake of Vitamin B12 is through these cells. While the exact processes that occur within these enterocytes are not fully understood, the cobalamin appears bound to transcobalamin II (TCII) in the portal blood (Srinivasan et al., 2006). The TCII-cobalamin complex is rapidly cleared due to specific binding sites on numerous cells. Internalization of TCII-cobalamin leads to dissociation of the complex and conversion of the cobalamin into its physiologically active forms (Srinivasan et al., 2006). Both transcobalamin and intrinsic factor bind cobalamin in a base-on conformation, however the binding mode for haptocorrin depends on the lower axial ligand, this allows for the clearance of analogous to Vitamin B12 from the blood through selective binding to the haptocorrin transport protein (Gherasim et al., 2013).
The two forms of cobalamin that are found in the human body both have differing physiological roles. Adenosylcobalamin acts as a coenzyme of methylmaloyl-CoA mutase, the main function of this protein is the conversion of methymalonyl-CoA to succinyl-CoA (Briani et al., 2013). Methylcobalamin works as a co-enzyme of methionine synthetase which catalyses the movement of the methyl group of the cobalamin molecule to homocysteine thus forming methionine, methylcobalamin is regenerated by further methyl group transfer (Iughetti et al., 2011). Methionine undergoes further biochemical processing to form adenosyl-methionine, a methyl group donator responsible for the methylation of many proteins, neurotransmitters and nucleic acids (Gherasim et al., 2013). The metabolism of methionin synthase requires a balance of carbon molecules which can lead either towards synthesis of DNA and RNA or the methylation of substrate compounds by S-adenosylmethionine (SAM) (McGovern et al., 2008). The role of Cbl in this function may therefore alter some epigenetic properties of an individual through specific methylation of DNA, RNA, histone and gene expression which may result in a variety of physiological differences (Gnimpieba et al., 2011).
Clinical presentations of Vitamin B12 deficiency are difficult to identify as being a unique symptom of the condition. One of the most common presentations is a feeling of fatigue or “general tiredness”; this relates to the role that Vitamin B12 plays in the regulation of sleep patterns (Iughetti et al., 2011). Further long term presentations may include neuropathy of the feet as well as (in very deficient cases) the development of anaemia. A key problem area in the identification of Vitamin B12 deficiency is the over lapping symptomatic expressions with diabetes (Briani et al., 2013). Unexplained fatigue may be attributed to low sugar levels as a result of medication or alterations in diet or eating habits and therefore may be misinterpreted as other problems. Neuropathy as a result of Vitamin B12 deficiency is particularly difficult to identify as it mimics that of diabetic neuropathy and can take a long period of time to develop (Iughetti et al., 2011). The currently used biochemical markers for diagnosis of Vitamin B12 deficiency are under much debate. The traditional serum Vitamin B12 assessment has been suggested to not be sufficient in predicting the presence of Vitamin B12 deficiency (Obeid et al., 2013).