Liver riboflavin metabolism

Figure 37.1 Riboflavin metabolism and cellular processing pathways. (A) Riboflavin and flavin intake is made via the diet, either in riboflavin-rich aliments or flavoproteins. In the latter, digestion in the stomach releases FAD and FMN cofactors. Riboflavin and flavins achieve a high concentration in the liver, spleen and cardiac muscle a concentration of about 30 nM riboflavin is also reached in the plasma circulation. (B) Riboflavin is imported into the cell and into the mitochondria via specific transporters (white circles in membranes). In the cytoplasm, flavin kinase (FK) and FAD synthetase (FADS) consecutively convert riboflavin into FMN and FAD, at the expense of ATP. An identical mechanism is also thought to be present inside the mitochondria, although a mitochondrial FK remains to be identified. FAD can also be imported into the mitochondria, or diffuse passively when the riboflavin concentrations are high. Figures reprinted from Henriques et al. (2010), with permission.

Vitamin Bj (8.44, riboflavin) is a benzopteridine derivative carrying a ribityl (reduced ribose) side chain. It occurs in almost all foods, the largest amounts being found in eggs, meat, spinach, liver, yeast, and milk. Riboflavin is one of the major electron carriers as a component of flavine-adenine dinucleotide (FAD), which is involved in carbohydrate and fatty acid metabolism. A hydride ion and a proton are added to the pyrazine ring of... 

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. 

We have not pursued mechanisms but suggest that the enhancement of carcinogenesis may be related to a role for riboflavin in the activation of enzymatic processes involved with metabolic detoxification of MBN, similar to azo reductase and its role in the detoxification of 4-dimethylaminoazobenzene (32). In this case riboflavin activates azo reductase in the liver and this, in turn, is associated with decreased carcinogenicity. Conversely, when animals are deprived of riboflavin, there is less active enzyme present to detoxify the chemical and the induction of liver cancer is enhanced. A similar process may be functioning in our MBN, riboflavin deprived model but the exact nature of the mechanism requires additional research. 

Duerden JM and Bates CJ (1985) Effect of riboflavin deficiency on lipid metabolism of liver and brown adipose tissue of sucking rat pups. British Journal of Nutrition 53, 107-15. 

Vitamin B complex is the collective term for a number of water-soluble vitamins found particularly in dairy products, cereals and liver.Vitamin B (thiamine) is used by mouth for dietary supplement purposes and by injection in emergency treatment of Wernicke-Korsakoff syndrome. Vitamin B2 (riboflavin) is a constituent of the coenzyme FAD (flavine adenine dinucleotide) and FMN (flavine mononucleotide) and is therefore important in cellular respiration. Vitamin Be (pyridoxine) is a coenzyme for decarboxylases and transamination, and is concerned with many metabolic processes. Overdose causes peripheral neuropathy. It may be used medically for vomiting and radiation sickness and for premenstrual tension. Pyridoxine has a negative interaction with the therapeutic use of levodopa in parkinsonism by enhancing levodopa decarboxylation to dopamine in the periphery, which does not then reach the brain. The antitubercular drug isoniazid interferes with pyridoxine, and causes a deficiency leading to peripheral neuritis that may need to be corrected with dietary supplements. Vitamin B ... 

Uptake and Metabolism. The vitamin Bg family consists of pyridoxine, pyridoxal, pyridoxamine, pyridoxine phosphate, pyridoxal phosphate (PLP), and pyridoxamine phosphate (Fig. 8.33). The commercial form is pyridoxine. Pyridoxal phosphate is the coenzyme form. It and pyridoxamine phosphate are from animal tissues. Pyridoxine is from plant tissues. All phosphorylated forms are hydrolyzed in the intestinal tract by phosphatases before being absorbed passively. Conversion to the phosphorylated forms occurs in the liver. Notice that niacin (NAD) and riboflavin (FMN, FAD) are required for interconversion among the vitamin Bq family. The phosphorylated forms are transported to the cells where needed. The major excretory product is 4-pyr-idoxic acid. 

Vitamin B2 (riboflavin) occurs in green vegetables, yeast, liver, and milk, it is a constituent of the coenzymes FAD and FMN, which have an important role in the metabolism of all major nutrients as well as in the oxidative phosphorylation reactions of the electron transport chain. Deficiency of B2 causes inflammation of the tongue and lips, mouth sores, and conjimctivitis. 

In vitro uptake of riboflavin by liver cells was examined in rats (Aw et al. 1983) and human hepatocytes (HEP G2) (Said et al. 1998). Carrier-mediated mechanism of riboflavin uptake by HEP G2 cells occurred Kt = Q.A pM), inhibited by structural analogues of riboflavin as well as metabolic inhibitors and regulated by Ca " /calmodulin kinase. Details are presented in Tables 36.1-36.4. 

Role of Riboflavin. Riboflavin deficiency has been found to produce abnormaUties in the metabolism of tryptophan (307-311). The deficiency leads to an increased excretion in the urine of kynurenine, anthranilic acid, and kynurenic acid and its conjugates (308, 309). In liver and kidney slices riboflavin deficiency leads to a decrease in indolepyruvic acid accumulation and an increase in the production of kynurenic acid and anthranilic acid from L-kynurenine (310, 311). The deficiency was also found to... 

Different enzymes and different tissue sites differ in the tenacity with which they can retain flavin coenzymes in times of riboflavin deficiency, so there is a characteristic pecking order for flavoen-zyme protection, which appears to reflect the metabolic importance of the different metabolic pathways affected. Apart from this pecking order, however, there is no repository of unused or nonfunctional riboflavin that can act as a store in times of dietary deficiency. Although some organs (such as liver) have relatively high concentrations of flavin enzymes, all of the flavin seems to be present as coenzyme moieties of flavin holoenzymes. Each tissue has a characteristic ceiling level of riboflavin at saturation, and a floor level characteristic of severe depletion, and these are determined, respectively, by the total amount of apoflavoprotein, and the amount of resistant holoenzyme, which cannot be depleted of its cofactor during riboflavin deficiency. 

Disturbances in fatty acid oxidation by isolated mitochondria, e.g., from livers of deficient animals, have been demonstrated, and one of the most characteristic metabolic changes, observed even in a mild deficiency state in experimental animals, is the appearance of abnormal dicarboxylic acids, and their derivatives, in the urine. These products seem to arise because fatty acyl intermediates become diverted away from the usual pathway of mitochondrial beta-oxidation, towards abnormal partial oxidation in the peroxisomes (which are less severely affected by the riboflavin deficiency state). 

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