Liver folic acid

Spinach, salad, cereal germ, and bran as well as pulses are good sources of folic acid. Liver and yeast contain high amounts of this vitamin, too, but are not consumed frequently enough to be relevant for the coverage of daily requirements [1,2]. 

Pteroylglutamic acid, see also under Folic acid. Liver L. casei factor, VI, 64,83, 198... 

Johnson et al. (1950) also observed the effects of deficiency of vitamin Bi2 and folic acid in the pig, and concluded that both substances were involved in hemopoiesis. This recalls the pigs described by Heinle et al. (1948), which were so completely depleted of hemopoietic factors that folic acid failed unless liver extract was supplied and liver extract failed unless small amounts of folic acid were supplied. The effect of folic acid, liver extract, and vitamin Bis on hemoglobin regeneration in chicks is discussed by Nichol et al. (1949). 

Folic acid is a member of the vitamin B complex found in green plants, fresh fruit, yeast, and liver. Folic acid takes its name from folium, Latin for leaf. Pterin compounds are named from the Greek word for wing because these substances were first identified in insect wings. Two pterins are familiar to any child who has seen (and chased) the common yellow sulfur butterfly and its white counterpart, the cabbage butterfly. Xanthopterin and leu-... 

Folic acid Green vegetables, liver, yeast, fruits... 

Toxicities are GI (stomatitis, diarrhea, nausea, vomiting), hematologic (thrombocytopenia, leukopenia), pulmonary (fibrosis, pneumonitis), and hepatic (elevated enzymes, rare cirrhosis). Concomitant folic acid may reduce some adverse effects without loss of efficacy. Liver injury tests (aspartate aminotransferase or alanine aminotransferase) should be monitored periodically, but a liver biopsy is recommended during therapy only in patients with persistently elevated hepatic enzymes. MTX is teratogenic, and patients should use contraception and discontinue the drug if conception is planned. 

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

Eolates are present in nearly all natural foods. Those with the highest folate content include yeast, liver and other organ meats, fresh green vegetables and some fresh fruits. The term folic acid arose from its first identification in leafy vegetables (e.g. spinach). 

Orotic acid in the diet (usually at a concentration of 1 per cent) can induce a deficiency of adenine and pyridine nucleotides in rat liver (but not in mouse or chick liver). The consequence is to inhibit secretion of lipoprotein into the blood, followed by the depression of plasma lipids, then in the accumulation of triglycerides and cholesterol in the liver (fatty liver) [141 — 161], This effect is not prevented by folic acid, vitamin B12, choline, methionine or inositol [141, 144], but can be prevented or rapidly reversed by the addition of a small amount of adenine to the diets [146, 147, 149, 152, 162]. The action of orotic acid can also be inhibited by calcium lactate in combination with lactose [163]. It was originally believed that the adenine deficiency produced by orotic acid was caused by an inhibition of the reaction of PRPP with glutamine in the de novo purine synthesis, since large amounts of PRPP are utilized for the conversion of orotic acid to uridine-5 -phosphate. However, incorporation studies of glycine-1- C in livers of orotic acid-fed rats revealed that the inhibition is caused rather by a depletion of the PRPP available for reaction with glutamine than by an effect on the condensation itself [160]. 

These three compounds exert many similar effects in nucleotide metabolism of chicks and rats [167]. They cause an increase of the liver RNA content and of the nucleotide content of the acid-soluble fraction in chicks [168], as well as an increase in rate of turnover of these polynucleotide structures [169,170]. Further experiments in chicks indicate that orotic acid, vitamin B12 and methionine exert a certain action on the activity of liver deoxyribonuclease, but have no effect on ribonuclease. Their effect is believed to be on the biosynthetic process rather than on catabolism [171]. Both orotic acid and vitamin Bu increase the levels of dihydrofolate reductase (EC 1.5.1.4), formyltetrahydrofolate synthetase and serine hydroxymethyl transferase in the chicken liver when added in diet. It is believed that orotic acid may act directly on the enzymes involved in the synthesis and interconversion of one-carbon folic acid derivatives [172]. The protein incorporation of serine, but not of leucine or methionine, is increased in the presence of either orotic acid or vitamin B12 [173]. In addition, these two compounds also exert a similar effect on the increased formate incorporation into the RNA of liver cell fractions in chicks [174—176]. It is therefore postulated that there may be a common role of orotic acid and vitamin Bj2 at the level of the transcription process in m-RNA biosynthesis [174—176]. 

Storage. The liver not only stores energy reserves and nutrients for the body, but also certain mineral substances, trace elements, and vitamins, including iron, retinol, and vitamins A, D, K, folic acid, and Bi2. 

Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose peak levels are generally reached within 1 hour. After IV administration, the drug is rapidly cleared from the plasma. Folic acid is metabolized in the liver. Normal serum levels of total folate have been reported to be 5 to 15 ng/mL normal CSF levels are approximately 16 to 21 ng/mL. In general, folate serum levels less than 5 ng/mL indicate folate deficiency, and levels less than 2 ng/mL usually result in megaloblastic anemia. A majority of the metabolic products appeared in the urine after 6 hours excretion was generally complete within 24 hours. 

Fig. 1. Folate-cobalamin interaction in the synthesis of purines and pyrimidines and, therefore, of DNA. (1) In gastrointestinal mucosa cells (2) in the liver (3) in peripheral tissues. C, cobalamine DAC, desoxyadenosylcobalamine HC, hydroxy cobalamine MC, methylcobalamine F, folic acid MTHF, methyltetrahydrofolic acid THF, tetrahydrofolic acid DHF, dihydrofolic acid dUMP, deoxyuridinemonophosphate dTMP, deoxythymidine-monophosphate. (Adapted from Far-...

About 10-25%, i.e. 50-200 pg, of the daily dietary intake of folic acid in yeasts, liver, and green vegetables is absorbed via active and passive transport in the proximal jejunum. As humans do not have dihydropteroate synthetase, which synthesizes folic acid in bacteria, we require folic acid in the diet. Only small amounts of folate can be stored in the body and dietary deficiency for only a few days can result in symptomatic folate deficiency. 

Cyanocobalamin, or vitamin B12, is in small amounts required for red blood cell production and for the formation of nucleoproteins and proteins. It is also needed for the proper functioning of the nervous system. Folic acid supplements can correct the anemia associated with vitamin B12 deflciency. Unfortunately, folic acid will not correct changes in the nervous system that result from vitamin B12 deficiency. Vitamin B12 is only found in animal sources such as liver and other organs. Some vitamin B12 is obtained from fish, eggs and milk. Folic acid and cyanocobalamin have been discussed in more detail in Chapter 22. 

Ascorbic acid or vitamin C is found in fruits, especially citrus fruits, and in fresh vegetables. Man is one of the few mammals unable to manufacture vitamin C in the liver. It is essential for the formation of collagen as it is a cofactor for the conversion of proline and lysine residues to hydroxyproline and hydroxylysine. It is also a cofactor for carnitine synthesis, for the conversion of folic acid to folinic acid and for the hydroxylation of dopamine to form norepinephrine. Being a lactone with two hydroxyl groups which can be oxidized to two keto groups forming dehydroascorbic acid, ascorbic acid is also an anti-oxidant. By reducing ferric iron to the ferrous state in the stomach, ascorbic acid promotes iron absorption. 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

Most of the oral formulations contain one of the iron compound with many vitamins, amino acids, liver extract, minerals, folic acid, appetite stimulants (cyproheptadine like compound). 

Alcohol indirectly affects hematopoiesis through metabolic and nutritional effects and may also directly inhibit the proliferation of all cellular elements in bone marrow. The most common hematologic disorder seen in chronic drinkers is mild anemia resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result from gastrointestinal bleeding. Alcohol has also been implicated as a cause of several hemolytic syndromes, some of which are associated with hyperlipidemia and severe liver disease. 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Patients with alcohol dependence and patients with liver disease can develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Patients who require renal dialysis develop folic acid deficiency because folates are removed from the plasma during the dialysis procedure. 

Parenteral administration of folic acid is rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes. A dose of 1 mg folic acid orally daily is sufficient to reverse megaloblastic anemia, restore normal serum folate levels, and replenish body stores of folates in almost all patients. Therapy should be continued until the underlying cause of the deficiency is removed or corrected. Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy. Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis. 

Nausea and mucosal ulcers are the most common toxicities. Progressive dose-related hepatotoxicity in the form of enzyme elevation occurs frequently, but cirrhosis is rare (< 1%). Liver toxicity is not related to serum methotrexate concentrations, and liver biopsy follow-up is only recommended every 5 years. A rare hypersensitivity-like lung reaction with acute shortness of breath is documented, as are pseudolymphomatous reactions. The incidence of gastrointestinal and liver function test abnormalities can be reduced by the use of leucovorin 24 hours after each weekly dose or by the use of daily folic acid, although this may decrease the efficacy of the methotrexate. This drug is contraindicated in pregnancy. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

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