Tissue Retinoid Metabolism

Tissues obtain retinol from holo-RBP throughout the day, and retinyl esters from chylomicrons and chylo-micron remnants after consumption of vitamin A-containing meals. Although the majority of the body's vitamin A is stored in the liver, many organs contain small reserves of retinyl esters. These small local supplies are believed to be critical for the generation of bioactive retinoids, formed through oxidative metabolism (Figure 2). Retinol that is liberated by the hydrolysis of retinyl esters is oxidized to retinoic acid in a two-step process in which retinal is an obligate intermediate. The oxidation of retinol to retinal has been attributed to several enzymes of the alcohol dehydrogenase and the short-chain dehy-drogenase/reductase gene families. Both of these types of enzymes also oxidize other substrates and the specifics of retinol oxidation in various tissues have been difficult to define. It is likely that the CRBP proteins function as chaperones for retinol during its oxidative metabolism. Since retinal can be reduced to form retinol, the retinal that is generated from the metabolism of carotenoids can give rise to retinyl esters and all of the other metabolites of reti-nol (see Figure 2). In the second oxidative step, which is irreversible, retinal is converted to retinoic acid. This step also may be catalyzed by several enzymes. Retinoic acid is present, sometimes in several isomeric forms, at nanomolar concentrations in many tissues. Its half-life is very short, a few hours or less, which implies that it is produced continuously to maintain tissue retinoic acid levels.

The /3-ionone ring of retinol and retinoic acid also can be oxidized, usually at carbon 4 to form 4-hydroxy and 4-oxo metabolites. The metabolism of retinoic acid is, in part, autoregulated due to the ability of retinoic acid to induce the expression of cytochrome P450 enzymes that form 4-oxo derivatives of retinoic acid. At this time, although limited evidence suggests that ring-oxidized retinoids still possess bioactivity, most evidence supports the thinking that they are metabolites in a catabolic pathway, destined for excretion. Ring-oxidized metabolites, which are normally present in plasma in low concentrations, are readily removed by the liver and conjugated with glucuronic acid, which makes them soluble in water. Glucuronides comprise a substantial fraction of the total retinoid excreted in bile and eliminated by the fecal route.

Production and oxidation both serve to maintain normal tissue retinoid levels. Nonetheless, these physiological processes can be overwhelmed by an excess of dietary vitamin A, resulting in excessive vitamin A in tissues and plasma, or by the use of synthetic retinoids that lead to substantial elevations in tissue bioactive retinoids (see the article section 'Hypervi-taminosis A and Vitamin A Toxicity').

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