Retinol liver metabolism

The effect of inhibitors on the biosynthesis of rubixanthin (114) and other hydroxylated carotenoids was studiedin Staphylococcus aureus. Retinol was metabolized in rat livers to give an acidic product which was allegedly different from retinoic acid. 

The retinyl esters are incorporated into chylomicrons, which in turn enter the lymph. Once in the general circula-tion. chylomicrons arc converted into chylomicron remnants, which arc cleared primarily by the liver. As the c.stcrs enter the hepalocytes. they are hydrolyzed. In the endoplasmic reticulum, the retinol is bound to retinol-binding protein (RBP). This cotnplex is released into the blood or transferred to liver stellate cells fur storage. Within the stellate cells, the retinol is bound to CRBP(I) and e.stcnTicd for storage by ARAT and LRAT. Stellate cells contain up to 95% of the liver vitamin A. stores. The RBP-retinol complex released into the general circulation from hepalocytes or stellate cells, in turn, is bound to transthyretin (TTR), which protects retinol from metabolism and renal excretion. ... 

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

The overall metabolism of vitamin A in the body is regulated by esterases. Dietary retinyl esters are hydrolyzed enzymatically in the intestinal lumen, and free retinol enters the enterocyte, where it is re-esterified. The resulting esters are then packed into chylomicrons delivered via the lymphatic system to the liver, where they are again hydrolyzed and re-esterified for storage. Prior to mobilization from the liver, the retinyl esters are hydrolyzed, and free retinol is complexed with the retinol-binding protein for secretion from the liver [101]. Different esterases are involved in this sequence. Hydrolysis of dietary retinyl esters in the lumen is catalyzed by pancreatic sterol esterase (steryl-ester acylhydrolase, cholesterol esterase, EC 3.1.1.13) [102], A bile salt independent retinyl-palmitate esterase (EC 3.1.1.21) located in the liver cell plasma hydrolyzes retinyl esters delivered to the liver by chylomicrons. Another neutral retinyl ester hydrolase has been found in the nuclear and cytosolic fractions of liver homogenates. This enzyme is stimulated by bile salts and has properties nearly identical to those observed for... 

Vitamin Ai (retinol) is derived in mammals by oxidative metabolism of plant-derived dietary carotenoids in the liver, especially -carotene. Green vegetables and rich plant sources such as carrots help to provide us with adequate levels. Oxidative cleavage of the central double bond of -carotene provides two molecules of the aldehyde retinal, which is subsequently reduced to the alcohol retinol. Vitamin Ai is also found in a number of foodstuffs of animal origin, especially eggs and dairy products. Some structurally related compounds, including retinal, are also included in the A group of vitamins. 

Pharmacokinetics Rapidly absorbed from the GI tract if bile salts, pancreatic lipase, protein, and dietary fat are present. Transported in blood to the liver, where it s metabolized stored in parenchymal hepatic cells, then transported in plasma as retinol, as needed. Excreted primarily in bile and, to a lesser extent, in urine. 

Altered vitamin A homeostasis, primarily manifested as decreased hepatic storage of vitamin A, is another established effect of PBBs in animals. Vitamin A is essential for normal growth and cell differentiation, particularly differentiation of epithelial cells, and some PBB-induced epithelial lesions resemble those produced by vitamin A deficiency. Because it is the primary storage site for vitamin A, the liver has a major role in retinol metabolism. Esterification of dietary vitamin A, hydrolysis of stored vitamin A, mobilization and release into the blood of vitamin A bound to retinol-binding protein, and much of the synthesis of retinol-binding protein occurs in the liver. 

The leveisal of the oxidative pathway of vitamin A (retinol —r retinal —>-retinoic add) does not occur in the body, When retinoic acid is feci to animals, even in relatively large doses, there is no storage and, in fact, die molecule is rapidly metabolized and cannot be found several hours after administration. The metabolic products have not been fully identified. Several fractions from liver or intestine, isolated after administering retinoic add marked with carbon-14, have been shown to have biological activity. 

Plants are the major source for dietary provitamin A. As mammals and humans cannot synthesize carotenoids, dietary provitamin A is obtained from plant sources that contain carotenoids having 2,6,6-trimethyl-l-cyclohexen-l-yl rings, such as P-carotene. More than 600 carotenoids have been identified in plants and algae, which together biosynthesize about 0.1 billion tons of carotenoids each year. However, only about ten carotenoids, including P-carotene, are nutritionally significant members of the provitamin A class that can be oxidatively metabolized to retinal in mammals and humans by such organs as the intestine, liver, and kidney and then reduced to retinol. 

We had previously eliminated the possibility that retinol affected bacterial viability in this assay. The likelihood of a non-specific inhibitory effect of retinol was also eliminated, since there was no effect of vitamin A alcohol on mutagenicity induced by adriamycin, a direct-acting mutagen in Salmonella (23). Thus, these findings demonstrated that retinol inhibited the metabolism of 2-fluorenamine by rat liver tissue preparations to forms capable of producing mutations in S typhimurium. 

The retinoids involved specifically in vision do not relate to the same chemical receptors as those found in the nutrition aspects of pharmacology. There is a different set of chemical receptors involved in the transport of retinol from the liver to the RPE cells of the retina. These receptors are found on the surface of the RPE cells and are specific for the retinoid binding proteins (RBP s) that transport the retinoids to the RPE. These RBP s play a unique role in the chromophore forming process that is not shared with the transport of retinol for purposes of metabolism and growth. Machlin says there are as many as 50,000 RBP receptor sites on the exposed surface of each RPE cell212. 

Retinoic acid is a metabolite of retinol in the liver, intestine, and bile of rat, and of retinyl acetate in the kidney and blood,378 and studies have been reported concerning the metabolism of retinoic acid and of vitamin A in various tissues of rats that are deficient in vitamin A.379... 

Leo MA and Lieber CS (1985) New pathway for retinol metabolism in liver microsomes. Journal of Biological Chemistry 260, 5228-31. 

Leo MA, Lasker JM, Raucy JL, Kim Cl, BlackM, and Lieber CS (1989) Metabolism of retinol and retinoic acid by human liver cytochrome P450IIC8. Archives of Biochemistry and Biophysics 269,305-12. 

Biochemical research has shown the importance of zinc metabolism in the retina (9). Zinc is found in high concentrations in the choroid, the retina, and especially the ganglion cells. Retinol dehydrogenase, a zinc-containing enzyme, interferes with the transformation of retinol (vitamin Ai), which is essential for color sensation and conal vision. Furthermore, zinc is involved in the biosynthesis of the specific transport of retinol from the liver to the effector cells. Ethambutol is a chelating... 

Vitamin A is readily absorbed from the intestine as retinyl esters. Peak serum levels are reached 4 h after ingestion of a therapeutic dose. The vitamin is distributed to the general circulation via the lymph and thoracic ducts. Ninety percent of vitamin A is stored in the liver, from which it is mobilized as the free alcohol, retinol. Ninety-five percent is carried bound to plasma proteins, the retinol-binding protein. Vitamin A undergoes hepatic metabolism as a first-order process. Vitamin A is excreted via the feces and urine. Beta carotene is converted to retinol in the wall of the small intestine. Retinol can be converted into retinoic acid and excreted into the bile and feces. The elimination half-life is 9 h. 

Fig. 1. The structures of key retinoids and their precursors. Fish convert retinyl esters (e.g. retinyl palmitate (RP)) and carotenoids (e.g. /3-carotene) to retinol in the gut lumen prior to intestinal absorption. Retinyl esters (e.g. RP) stored in the liver are synthesized from retinol by lecithin retinol acyltransferase (LRAT) and acyl CoAiretinol acyltransferase (ARAT). The retinyl esters are mobilized through their conversion to retinol by retinyl ester hydrolase (REH), which is then transported in the circulation to various sites in the body. Retinol is further metabolized within specific tissues to retinal by alcohol dehydrogenases (ADH) or short-chain dehydrogenase/reductase. Retinal is converted to the two major biologically active forms of retinoic acid (RA) (all-trans and 9-cis RA). Retinaldehyde dehydrogenase 2 (Raldh2) synthesizes all-trans RA from all-trans precursors and 9-cis RA form 9-cis precursors.

Fig. 2. Tissue distribution and metabolism of retinoids in fish. Dietary carotenoids (e.g. /3-carotene (/3C)) and retinyl esters (e.g. retinyl palmitate (RP)) are converted into retinol (Rol) in the lumen of the gut. Retinol is then re-esterified and packaged into chylomicrons and transported to the portal circulation. When required elsewhere, stored retinyl esters (e.g. RP) in the liver are hydrolyzed to retinol and transported in the blood bound to the retinol-binding protein (RBP). Retinol is converted in target tissues to RA, RP or retinal (Ral). RA may exert its effects locally, or be returned to the circulation and transported throughout the body bound to albumin. RA can then be sequestered in other tissues.

Prealbumin is the transport protein for thyroxine and a carrier for retinol-binding protein. The body s content of prealbumin is low (10 mg/kg of body weight), and it has a very short biologic half-fife (I to 2 days). Prealbiunin may be reduced in as few as 3 days after calorie and protein intake is significantly decreased, or when hypercatabolism or severe metabolic stress (tramna or bmns) is present. Because of its short half-life, it is most useful in monitoring the shortterm, acute effects of nutrition support. As with ALB and TFN, sermn prealbumin concentrations are depressed in those with liver disease due to decreased hepatic synthesis. Increased serum prealbumin concentrations have been noted in patients with renal disease due to impaired renal excretion. 

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