Retinol turnover

For the rats with low vitamin A status (liver vitamin A, <8 nmol), plasma retinol turnover rate was 12 times the irreversible disposal rate (5.8 nmol/ day) and an average retinol molecule receded to plasma 12 times before irreversible loss (Lewis et al., 1990). These parameters were similar to the values we had previously reported (Green et aL, 1985). The model (Lewis et al., 1990) predicted that only 7.5% of the predicted whole-body vitamin A was in the liver. Forty-four percent of plasma retinol turnover was predicted to be transferred to the kidneys and almost all of this was recycled. The model predicted that 47% of the vitamin A output was via urine and 53% via feces the irreversible loss data were very useful in identifying other model parameters. The model incorporates metabolite-, urinary-, and fecal-delay elements. More work needs to be done to model the sites of formation and rates of excretion of vitamin A metabolites. 

A small but variable proportion of the carotenoids with one or two P-ionone rings (mainly P-carotene) are cleaved in the enterocytes to produce retinol (vitamin A). This process is very tightly controlled, so that too much vitamin A is not produced, although the control mechanism is not clear. Some cleavage of P-carotene can also occur in the liver, but this does not account for the turnover of P-carotene in the body. Small amounts of carotenoids are subject to enterohepatic circulation, but this does not account for losses. 

Topical application of Cathepsin D-like enzyme from mushroom extract (Actizyme) has also been shown to be beneficial for the treatment of xerosis.47 In dry skin SC turnover is reduced. This parameter can be measured in vivo using the dansyl chloride test. Addition of this enzyme to a formulation increased SC turnover by about 30%. This was of similar order to the effect of hydroxyacids, retinol, and mechanical scrubbing. In contrast to these treatments use of the enzyme did not impair barrier function nor increase stinging scores. 

Measurements of the levels of semm proteins such as albumin, transthyretin (also known as prealbumin), transferrin and retinol-binding protein are used as biochemical parameters in the assessment of protein energy malnutrition (Table 17-1). An ideal protein marker should have rapid turnover and present in sufficiently high concentrations in semm to be measured accurately. Transthyretin has these properties it is a sensitive indicator of protein deficiency and is effective in assessing improvement with refeeding. 

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-... 

Fast turnover liver retinyl ester Retinol-binding protein retinol 2.74 0.11 13.9... 

Slow turnover liver retinyl Retinol-binding protein retinol 0.041 0.11 13.2... 

Retinol-binding protein retinol Fast turnover liver retinyl ester 2.99 0.21 26.4... 

The fast turnover liver -carotene-dg curve exhibits a narrow peak after ingestion of the experimental dose, and it is similar to the predicted fast turnover liver retinoid-d4 curve. The slow turnover liver /8-carotene-dg peak is broader than the fast turnover liver /3-carotene-dg peak and decays to near zero in approximately 50 days after ingestion of the labeled dose. Notice that the slow turnover liver -carotene-dg level does not remain elevated as long as the slow turnover liver retinol-d4. The slow turnover liver /3-carotene decays in a fashion similar to the slow turnover liver /3-carotene-dg, as expected, since the /3-carotene-dg is the source of the elevated slow turnover liver /3-carotene. 

FIG. 7. Compartmental model predicted masses and concentrations of retinol and retinyl ester in plasma, liver, and extrahepatic tissue of a healthy adult who ingested a single 73-/imol dose of /S-carotene-dn orally. The Fast turnover liver retinoid (bottom left) and Slow turnover liver retinoid (bottom right) each include the protio and deuterated species. 

The moderate depression in carrier proteins could be the consequence of either an increased rate of catabolism consequential to an elevated metabolic rate or a decreased rate of hepatic synthesis and mobilization. Although early animal studies gave inconsistent results (Johnson and Baumann, 1948 Anderson et aL, 1964), the weight of evidence suggests that an increased metabolic rate significantly increases the rate of vitamin A utilization. The observations in humans of depressed circulating levels of vitamin A and its carrier proteins in febrile conditions (Arroyave and Calcano, 1979) are in accord with this hypothesis. An increased utilization of retinol would increase the turnover of RBP also, since apo-RBP normally has a short transient time in the circulation. 

Zinc deficiency accompanied by a depression in plasma retinol has been noted in several studies. Some investigators have reported an increased liver vitamin A in several species of zinc-deficient animals (Stevenson and Earle, 1956 Saraswat and Arora, 1972 J. C. Smith et aL, 1973, 1976 Brown et aL, 1976 Jacobs et al., 1978 Carney et aL, 1976). There are also reports in humans in an association between lowered zinc, retinol, and RBP (Jacobs et a/., 1978 Solomons and Russell, 1980). J. C. Smith et al, (1973) suggested that hepatic mobilization of vitamin A was impaired by zinc deficiency and their follow-up studies demonstrated a depression in liver and plasma RBP in the zinc-deficient rat compared to pair-fed controls (Brown et al., 1976 Smith et al., 1974). The depression was hypothesized to be the result of a depressed synthesis rather than an increased turnover of RBP. That preformed RBP is present in zinc-deficient rats was demonstrated by Carney et al. (1976) using labeled vitamin A. Zinc-deficient rats, whether or not they were also vitamin A-deficient, were able to mobilize over a short time span a small oral dose of vitamin A as well as could their pair-fed controls. Those animals deficient only in zinc excreted metabolites of the labeled vitamin in a similar quantitative manner as the pair-fed controls for 6 days postdosing. These data suggest that the release of retinol from retinyl ester stores, as well as a depressed RBP synthetic rate, contributed to low plasma levels of vitamin A in zinc deficiency. 

The tissue distribution and levels of RBP in normal and in retinol-deficient rats were measured in order to explore the role of different tissues in the metabolism of RBP (J. E. Smith et al., 1975). The tissues examined included liver, kidney, fat, muscle, brain, eye, salivary gland, thymus, lung, heart, intestine, spleen, adrenal, testes, thyroid, and red blood cells. The RBP levels were low or very low in tissues other than liver, kidney, and serum and varied from 12 p.g/g of tissue for normal spleen to an undectable level in red blood cells. Much of the RBP in the tissues with low levels was most likely due to residual serum in the samples. In general, except for liver, RBP levels were lower in tissues from retinol-deficient rats than in those fixim normal rats. In normal rats, the liver, kidney, and serum levels were 30 4 (mean SEM), 151 22, and 44 3 p.g/g, respectively. In retinol-deficient rats, the liver RBP level was about three times the normal level whereas the kidney and serum levels were about one-fifth the normal values. It was suggested that die levels of RBP in normal as compared to deficient liver, serum, and kidney appear to reflect the relative rates of RBP secretion and turnover (see later discussion). 

The estimated total body turnover rate of RBP can be compared with available estimates for total body vitamin A utilization and turnover in normal well-nourished adults. A body turnover rate for RBP of about 5 mg kg day is equivalent to 16-17 pmol turnover per day for a 70-kg man. A comparable turnover for retinol would represent the daily turnover of 4.6-4.S mg, or approx-... 

Two independent families have been described in the literature that have abnormally low blood RBP-ROH levels [114-117]. In one family from Japan, several members reportedly have serum RBP-ROH levels that are approximately 50% that of normal [114-116]. These diminished RBP-ROH levels did not respond to oral administration of retinol or to a protein-rich diet [114-116]. RBP isolated from one affected member of this family demonstrated no differences in its molecular weight, isoelectric point, binding to TTR or immunological properties as compared to RBP isolated from unaffected family members [114-116]. At present it is not clear whether the diminished RBP-ROH levels measured in these individuals arises from some defect in the gene for RBP or if the defect exists in another gene that has an important influence on the normal physiology of RBP-ROH (i.e. on RBP synthesis, secretion, turnover or catabolism). 

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