Retinoic acid retinoids

The large group of steroid, retinoic acid (retinoid), and thyroid hormones exert at least part of their effects by a mechanism fundamentally different from that of other hormones they act in the nucleus to alter gene expression. We therefore discuss their mode of action in detail in Chapter 28, along with other mechanisms for regulating gene expression. Here we give a brief overview. 

Because of the presence of an extended polyene chain, the chemical and physical properties of the retinoids and carotenoids are dominated by this feature. Vitamin A and related substances are yellow compounds which are unstable in the presence of oxygen and light. This decay can be accelerated by heat and trace metals. Retinol is stable to base but is subject to acid-cataly2ed dehydration in the presence of dilute acids to yield anhydrovitamin A [1224-18-8] (16). Retro-vitamin A [16729-22-9] (17) is obtained by treatment of retinol in the presence of concentrated hydrobromic acid. In the case of retinoic acid and retinal, reisomerization is possible after conversion to appropriate derivatives such as the acid chloride or the hydroquinone adduct. Table 1 Hsts the physical properties of -carotene [7235-40-7] and vitamin A. 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

Retinoids are needed for cellular differentiation and skin growth. Some retinoids even exert a prophylactic effect on preneoplastic and malignant skin lesions. Fenretlnide (54) is somewhat more selective and less toxic than retinyl acetate (vitamin A acetate) for this purpose. It is synthesized by reaction of all trans-retinoic acid (53), via its acid chloride, with g-aminophe-nol to give ester 54 (13). 

Agents which enhance the host s response against neoplasias or force them to differentiate are termed biological response modifiers. Examples include interleukin 2 which is used to treat renal cell carcinoma, interferon a which is active against hematologic neoplasias, and tretinoin (all-trans retinoic acid) which is a powerful inducer of differentiation in certain leukemia cells by acting on retinoid receptors. Side effects include influenza like symptoms, changes in blood pressure and edema. 

Retinoic acid (RA) describes a group of vitamin A acid (synonym Vitamin A1 acid) derivatives such as all-irans-retinoic acid (tretinoin), 9-cis-retinoic acid and 13-cis retinoic acid (isotretinoin). Retinoic acids act through binding to retinoic acid and retinoid X response elements. 

The retinoid X receptor (RXR) is a nuclear receptor that binds and is activated by certain endogenous retinoids, such as 9-cis-retinoic acid. RXR is the obligatory heterodimerization partner for a large number of nonclassic steroid nuclear receptors, such as thyroid hoimone receptor, vitamin D3 receptor, peroxisome proliferator-activated receptor and pregnane X receptor. 

Retinoids Vitamin A Carotinoids Retinylesters Retinol Retinal Retinoic acid Vitamin A acid... 

Up to now, far more than 5000 retinoic acid analogs have been synthesized, out of which the following three generations have been established for therapy of various disorders First, the nonaromatic retinoids (3-carotene (provitamin A), alWraras-retinoic acid (RA) (tretinoin) and 13-cis-RA (isotretinoin), second, the monoaromatic retinoid derivatives trimethyl-methoxyphenyl analog of RA (etretinate) and9-(4-methoxy-2,3,6-trimethylphenyl)-... 

Among retinoids, 13-cis-retinoic acid is known to have not only anti-inflammatory but also sebostatic effects. Therefore it is one of the most potent topical and also systemic agents for therapy of acne. 

Drug treatment of photoaged skin can be categorized as antioxidants, a-hydroxy acids and topical retinoids. Of these three approaches only topical retinoids, particularly retinaldehyde and alWrans-retinoic acid, have a well documented ability to restorethe repair... 

Actinic keratoses were the first skin lesions to be treated topically with all-frans-retinoic acid. In various clinical trials, retinoids have been shown to be active in chemoprevention and treatment or prevention skin malignancies [2]. 

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. 

Systemic treatment of 13-cis retinoic acid frequently leads to cheilitis and eye irritations (e.g., unspecific cornea inflammation). Also other symptoms such as headache, pruritus, alopecia, pains of joints and bone, and exostosis formation have been reported. Notably, an increase of very low density lipoproteins and triglycerides accompanied by a decrease of the high density lipoproteins has been reported in 10-20% of treated patients. Transiently, liver function markers can increase during oral retinoid therapy. Etretinate causes the side effects of 13-cis retinoid acid at lower doses. In addition to this, generalized edema and centrilobulary toxic liver cell necrosis have been observed. 

Abu J, Batuwangala M, Herbert K et al (2005) Retinoic acid and retinoid receptors potential chemopreventive and therapeutic role in cervical cancer. Lancet Oncol 6 712-720... 

Retinoids (i.e., tretinoin and tazarotene) mediate cellular responses primarily through activation of nuclear retinoid receptors [rr]. There are two types of nuclear retinoic acid receptors the retinoic acid receptors (RARs) and the retinoid X receptors. Each type of receptor contains three receptor subtypes alpha, beta, and gamma [rr, 11]. Among the commonly prescribed retinoids, tretinoin activates the RARs alpha, beta, and gamma directly, and the retinoid X receptors indirectly (through conversion of tretinoin to 9-cis-retinoic acid) [rr, 13]. Conversely,... 

Kang S, Duell EA, Fisher GJ, et al (1995) Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristic of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol 105 549-556... 

A most important function of vitamin A is in the control of cell differentiation and mrnover. PsA-trans-retinoic acid and 9-cw-retinoic acid (Figure 45-1) regulate growth, development, and tissue differentiation they have different actions in different tissues. Like the steroid hormones and vitamin D, retinoic acid binds to nuclear receptors that bind to response elements of DNA and regulate the transcription of specific genes. There are two families of nuclear retinoid receptors the retinoic acid receptors (RARs) bind all-rrijw-retinoic acid or 9-c -retinoic acid, and the retinoid X receptors (RXRs) bind 9-cw-retinoic acid. 

Some 117 naturally occurring apo-carotenoids, 88 of which have been fully identified and another 6 naturally occurring seco-carotenoids have been referenced as carotenoids, thus representing around 15% of the carotenoids numbered to date (see Figure 3.3.1). This subfamily of carotenoids would be even larger if we consider the retinoids andnorisoprenoids. However, these compounds are excluded by nomenclature rules that dictate that they are not deemed to be carotenoids because of the absence of two central methyl groups (at C20 and C20 ). Retinoic acid, retinal. 

Vitamin A (retinol) and retinoic acid are carotenoid oxidation compounds that are very important for human health. The main functions of retinoids relate to vision and cellular differentiation. With the exception of retinoids, it was only about 10 years ago that other carotenoid oxidation products were first thought to possibly exert biological effects in humans and were implicated in the prevention - or promotion of degenerative diseases. A review on this subject was recently published. ... 

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