Retinoic acid turnover

Generally used at a concentration of 0.05-1% with minimal side effects (erythema and desquamation), retinoic acid has to be applied once a day, usually nightly. It does not suppress melanogenesis, but accelerates epidermal turnover. 

Tretinoin or retinoic acid is the acid form of vitamin A. Actually it is the all-trans isomer of retinoic acid. It is an effective topical agent for acne vulgaris. Its mechanism of action is believed to be associated with increased epidermal cell turnover. Some 10% of the topically applied dose is absorbed, metabolized by the liver and excreted in the urine and bile. To be effective tretinoin should be applied in a concentration that results in mild irritation and erythema. Patients should be advised to avoid or minimize sun exposure and use a protective sun screen as animal studies have raised some concern about possible carcinogenic effects under the influence of ultraviolet radiation. There are no indications that topical tretinoin is associated with an increased risk for birth defects. 

Retinoic acid has several effects on epithelial tissues. It stabilizes lysosomes, increases ribonucleic acid polymerase activity, increases prostaglandin E2, cAMP, and cGMP levels, and increases the incorporation of thymidine into DNA. Its action in acne has been attributed to decreased cohesion between epidermal cells and increased epidermal cell turnover. This is thought to result in the expulsion of open comedones and the transformation of closed comedones into open ones. 

Tissues contain two types of receptors for 1,25-dihydroxyvitamin D a classic steroid hormone nuclear receptor and a putative membrane receptor. 1,25-Dihydroxyvitamin D interacts with the nuclear receptor to form a receptor-ligand complex (Fig. 30-4). This complex then interacts with other nuclear proteins, such as the retinoic acid receptor (RXR) to form a functional transcription complex. The main effect of this transcription complex is to alter the amount of mRNAs coding for selected proteins such as cal-bindin, the calcium transport protein in the intestine, and the vitamin D receptor. In concert with PTH, 1,25-dihydroxyvitamin D acts to mobilize calcium from bone.As a consequence, serum calcium and phosphate homeostasis is maintained by a combination of 1,25-dihydroxyvitamin D stimulation of intestinal absorption and bone turnover. 

Tretinoin is also used as an antiwrinkle cream. There is disagreement on the mechanism and there may be more than one. Some improvement may be attributable to the irritation the drug causes. There is an increase in epidermal cell turnover, shedding older cells and thickening the skin. Also the drug may combine with epidermal retinoic acid receptors, thereby decreasing keratin production. Keratin can contribute to skin wrinkling (13). 

Tretinoin became available as a topical treatment for acne in the United States in 1971. Tretinoin is also known by its chemical name, z)X-trans-retinoic acid. It increases the turnover of skin cells at the surface of the hair follicle. This leads to the extrusion of comedones. Side effects include local skin irritation and increased stm sensitivity. Newer preparations of tretinoin, designed to achieve slow absorption of the drug into epithelial cells, cause less skin irritation than forms available initially. Improvement in acne may not be noticeable until two to three weeks after treatment begins. 

However, the relevance of these transformations to retinoic acid homeostasis in target tissues is not clear. White et probed a panel of mRNAs from mammalian cell lines with a cDNA from a zebrafish P450 shown to be involved in retinoic acid-inducible retinoic acid oxidation and characterized P450 26A1 (ref [1391]). The heterologously expressed enzyme converted all-traws-retinoic acid to the 4-hydroxy-, and 4-oxo-, and 18-hydroxy products. The turnover numbers are unknown because the amount of P450 was not quantified, but the enzyme is clearly able to catalyze the oxidation of sub-p,M additions of all-fraris-retinoic acid. Apparently other retinoic acid isomers are not substrates. 

AXEL, D. L, FRIGGE, A., DITTMANN, J., RUNGE, H., SPYRIDOPOULOS, L, RIESSEN, R., VIEBAHN, R. KARSCH, K. R. 2001. All-trans retinoic acid regulates proliferation, migration, differentiation, and extracellular matrix turnover of human arterial smooth muscle cells. Cardiovasc Res, 49, 851-62. 

The most important function of vitamin A is in the control of cell differentiation and turnover. All-/n j-retinoic acid and 9-ar-retinoic acid (Figure 11.3) act in the regulation of growth, development and tissue differentiation they have different actions in different tissues. Like the steroid hormones (section 10.4) and vitamin D (section 11.3.3), retinoic acid binds to nuclear receptors that bind to response elements (control regions) of DNA and regulate the transcription of specific genes. 

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