Retinoic acid , circulating levels

Lipid-soluble hormones act usually by gene activation/deactivation. Examples of these hormones include steroids, thyroid hormone, and vitamin A (retinoic acid). The hormones are transported through the circulation in association with a hormone-binding protein and are soluble in the plasma membrane of the cell. Their receptors are intracellular, and they act on gene transcription (the synthesis of messenger RNA) rather than at the protein level. Thus, they act more slowly than do the soluble hormones, on the scale of days rather than minutes. 

Dermac SR-38 is one of a series of oxazolidinones, cyclic urethane compounds, evaluated as transdermal enhancers. The compound was designed to mimic natural skin lipids (such as ceramides), to be nonirritating, and to be rapidly cleared from the systemic circulation following absorption. In animal and human safety studies, Dermac SR-38 demonstrated a good skin tolerance (no observed irritancy or sensitization at levels of 1-10 wt% moderate to severe irritation in rabbit at 100%), and a low degree of acute toxicity (LD50(rat oral) > 5.0g/kg). The compound was evaluated for its ability to enhance the human skin permeation of diverse drugs from dermal and transdermal delivery systems. Data for minoxidil indicated an enhancer concentration-dependent effect for permeation enhancement. Dermac SR-38 was also found to enhance the skin retention of both retinoic acid when applied in Retin A cream, and dihydroxyacetone when applied in a hydrophilic cream. ... 

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. 

Retinoic acid, an endogenous retinoid, is a potent inducer of cellular differentiation. Because cancer is fundamentally a loss of cellular differentiation, circulating levels of retinoic acid could play an important role in chemoprevention. However, physiological concentrations are typically below the limits of HPLC detection. Sensitive techniques, such as negative chemical ionization (NCI) GC/MS have been employed for quantification, but cause isomerization and also fail to resolve the cis and trans isomers of retinoic acid. Normal phase HPLC can resolve the cis and trans isomers of retinoic acid without isomerization, and mobile phase volatility makes it readily compatible with the mass spectrometer. Based on these considerations, a method combining microbore normal phase HPLC separation with NCI-MS detection was developed to quantify endogenous 13-cis and all-trans retinoic acid in human plasma. The limit of detection was 0.5 ng/ml, injecting only 8 pg of retinoic acid onto the column. The concentration of 13-cis retinoic acid in normal, fasted, human plasma (n=13) was 1.6 +/- 0.40 ng/ml. 

Since retinoic acid (and other acidic retinoids) circulates bound to albumin rather than to RBP, it is likely that retinoic acid is not delivered to tissues via a specific receptor-regulated process. Accordingly, one would anticipate that there might be a fairly close and consistent relationship between the dose of retinoic acid administered on the one hand and the rate of tissue delivery and risk of toxicity on the other. If this is true, then the plasma level of retinoic acid (or its analogs) should correlate well with the risk and development of toxicity and should provide a means of assessing and monitoring toxicity with these compounds in a clinical setting. 

The predominant retinoid in the fasting circulation is retinol, all of which is bound to its specific plasma transport protein, retinol-binding protein (RBP) [1,2]. Although retinol accounts for approximately 95 to 99% of all retinoid in the circulation, other retinoids also are present. Fasting human and rodent blood contains very low levels of both sAhtrans- and 13-cw-retinoic acid (approximately 0.2 to 0.7% of those of retinol) [3], as well as low levels of retinyl esters in lipoprotein fractions, particularly very low-density lipoproteins (VLDL) and low density lipoproteins (LDL) [4]. Soluble glucuronides of both retinol and retinoic acid are also detectable in the circulation of humans and rodents [5], as are provitamin A carotenoids like P-carotene... 

Following consumption of a retinoid-rich meal, the circulation can also contain large amounts of retinyl esters in chylomicrons and/or their remnants [6,7]. Postprandial retinyl ester concentrations can easily exceed fasting retinol levels by several fold [7, 8]. Moreover, consumption of a retinoid-rich meal brings about an increase in circulating concentrations of all-trans- and 13-cw retinoic acid and of glucuronides of both retinol and retinoic acid [7, 9]. 

Studies in rabbits indicate that the p-carotene content of the diet influences serum levels of all-rran -retinoic acid [16]. Dietary p-carotene, provided in graded doses over a nine-week period, was associated with higher serum concentrations of all-rran -retinoic acid. Thus, for the rabbit, not only is all- mn -retinoic acid present in the circulation, but levels of this active retinoid are influenced by p-carotene consumption. 

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