Retinoids depletion

Little is known of the mechanisms by which environmental chemicals deplete retinoid stores. In many field studies there is evidence of increased activity of phase I and II biotransformation enzymes, and both are thought to directly metabolize retinoids. P450 enzymes also produce oxyradicals causing oxidative stress34,72,73, which may lead to retinoid use as antioxidants. There was evidence of oxidative stress and retinoid depletion in lake trout inhabiting an area contaminated with iron-ore mine tailings80, yet it is unlikely that this exposure would be associated with induction of phase I or II biotransformation enzymes. 

In the dark-adapted eyes of most animals, the retinoid stores in the RPE represent between 1 and 6 mol Eq of the retinal visual pigment. It is not known whether the magnitude of these stores depends on the vitamin A status of the animal, although it is probable that they serve as a reserve that protects the visual system from retinoid depletion under conditions of dietary deficiency. Since these stores typically contain up to 75% 11-m-retinyl ester, the provision of 11-cis isomer for visual pigment synthesis may also be important under certain circumstances. However, the presence of this isomer in the RPE is not critical for regeneration, which can proceed efficiently in the absence of appreciable supplies of 11-cis-retinyl ester [see Bridges (1976b) for further discussion of this question]. 

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]. 

Foster I don t know the mechanism whereby chromophore is retained. The bottom line is that we know chromophore is only depleted in flies and mice, and that most of the retinoid will be part of the visual system anyway. There must be some other way of retaining vitamin A. In fact in mammals, there are a whole range of potential vitamin A binding proteins, hke IRBP in the pigmented epithelium, that could serve to mop-up and act as a chromophore sink. 

As detrimental effects result from deficiency as well as an excess of retinoids and carotenoids, and since both have similar adverse effects in terms of fibrosis, carcinogenesis, and possibly embryotoxicity, therapeutic measures must pay attention to the narrow therapeutic window, especially in drinkers, in whom alcohol narrows the therapeutic window even further by promoting the depletion of retinoids and by potentiating their toxicity (91). 

Several PHAHs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), co-planar PCBs (PCB 77 and PCB 126), 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 2,3,7,8-tetra-chlordibenzofuran (TCDF) affect the retinoid status of fish. Short-term exposures (< 4 weeks) do not appear to deplete retinoid stores. Besselink et al.12 exposed flounder (Platichthys flesus) to TCDD by oral gavage and found few changes in plasma and hepatic retinoids after 10 d, but there was a 27-fold increase of CYP1A activity. 

Accelerated metabolism and breakdown of retinoids may be another mechanism responsible for the depletion of retinoid stores following contaminant exposure. 

Alsop, D., M. Hewitt, M. Kohli, S. Brown and G. Van Der Kraak. Constituents within pulp mill effluent deplete retinoid stores in white sucker and bind to rainbow trout retinoic acid receptors and retinoid X receptors. Environ. Toxicol. Chem. 22 2969-2976, 2003. 

Retinoids, a group of compounds related to vitamin A which have profound effects on DNA transcription, have an inhibitory effect on cellular proliferation and have been implicated in cellular differentiation (35-37). It has been suggested that depletion of retinoic acid (RA) secondary to retinal detachment may result in morphologic and proliferative changes in RPE that ultimately lead to PVR (38). RA also markedly... 

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. ... 

In both cases, there was no evidence for depletion of the retinoid stored in the RPE. 

Depletion of plasma retinol and/or intracellular retinol metabolism results in compensatory elevation of intracellular retinol through mobilization of retinyl ester (RE). Mechanisms appear to include inhibition of LRAT and stimulation of RE hydrolysis by apo-CRBP [6-8]. Observation and partial purification of membrane-associated, bile salt-independent retinyl ester hydrolase (REH) provided insight into intracellular RE hydrolysis. This REH lacks activity for cholesterol esters, has reduced activity for triacylglycerol, and distributes widely in retinoid target tissues [9-11]. To date, two probable physiologically significant, bile salt-mdependent... 

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