Extrahepatic tissue vitamin

Both intact carotenoids and their apolar metabolites (retinyl esters) are secreted into the lymphatic system associated with CMs. In the blood circulation, CM particles undergo lipolysis, catalyzed by a lipoprotein lipase, resulting in the formation of CM remnants that are quickly taken up by the liver. In the liver, the remnant-associated carotenoid can be either (1) metabolized into vitamin A and other metabolites, (2) stored, (3) secreted with the bile, or (4) repackaged and released with VLDL particles. In the bloodstream, VLDLs are transformed to LDLs, and then HDLs by delipidation and the carotenoids associated with the lipoprotein particles are finally distributed to extrahepatic tissues (Figure 3.2.2). Time-course studies focusing on carotenoid appearances in different lipoprotein fractions after ingestion showed that CM carotenoid levels peak early (4 to 8 hr) whereas LDL and HDL carotenoid levels reach peaks later (16 to 24 hr). 

Release from the liver When needed, retinol is released from fie liver and transported to extrahepatic tissues by the plasma retax -binding protein (RBP). The retinol-RBP complex attaches to spe cific receptors on the surface of the cells of peripheral tissues, permitting retinol to enter. Many tissues contain a cellular letaiol-binding protein that carries retinol to sites in the nucleus where the vitamin acts in a manner analogous to steroid hormones. 

Menaquinones are synthesized by intestinal bacteria, but it is unclear how much they contribute to vitamin K nutrition, because they are extremely hydrophobic, and win only be absorbed from regions of the gastrointestinal tract where bUe salts are present - mainly the terminal Ueum. However, prolonged use of antibiotics can lead to vitamin K deficiency and the development of vitamin K-responsive hypoprothrombinemia (Section 5.4), as can dietary deprivation of phylloquinone. In vitro, menaquinones 2 to 6 have the same activity as phylloquinone as coenzyme for the solubilized liver microsomal vitamin K-dependent carboxylase (Section 5.3.1), whereas menaquinones with a side chain longer than seven have lower activity (Suttie, 1995). In extrahepatic tissues, the principal active vitamer is menaquinone-4 (Thijssen and Drittij-Reijnders, 1996 Thijssen et al., 1996). 

Several interesting hypotheses resulted from this model (Green et al, 1985). (1) Plasma retinol recycled 12 times before irreversible loss and its turnover rate (nmol/day) was 13 times the disposal rate (24 nmol/day). That is, in support of our previous results (Lewis et al, 1981), an average plasma retinol molecule apparently recycles many times before irreversible utilization. (2) In contrast to the belief that the liver is the sole source of plasma retinol/RBP, our model predicted that 55% of plasma retinol input was from the liver and 45% was from extrahepatic tissues. (3) The model predicted that, in these rats that had marginal liver vitamin A stores and that were in slight negative vitamin A balance, almost half of the whole-... 

The interaction between alcohol and vitamin A is complex. They have overlapping metabolic pathways a similar 2-step process is involved in the metabolism of both alcohol and vitamin A, with alcohol dehydrogenases and acetaldehyde dehydrogenases being implicated in the conversion of vitamin A to retinoic acid. Alcohol appears to act as a competitive inhibitor of vitamin A oxidation. In addition, chronic alcohol intake can induce cytochrome P450 isoenzymes that appear to increase the breakdown of vitamin A (retinol and retinoic acid) into more polar metabolites in the liver, which can cause hepatocyte death. So chronic alcohol consumption may enhance the intrinsic hepatotoxicity of high-dose vitamin A. Alcohol has also been shown to alter retinoid homoeostasis by increasing vitamin A mobilisation from the liver to extrahepatic tissues, which could result in depletion of hepatic stores of vitamin A. ... 

Induction of extrahepatic mdoleamine dioxygenase (which catalyzes the same reaction as tryptophan dioxygenase, albeit by a different mechanism) by bacterial lipopolysaccharides and mterferon-y may result in the production of relatively large amounts of kynurenine and hydroxykynurenine in tissues that lack the enzymes for onward metabolism. Kidney has kynurenine transaminase activity, and therefore extrahepatic metabolism of tryptophan may result in significant excretion of kynurenic and xanthurenic acids, even when vitamin Bg nutrition is adequate. 

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