Retinoids plasma

More specific methods involve chromatographic separation of the retinoids and carotenoids followed by an appropriate detection method. This subject has been reviewed (57). Typically, hplc techniques are used and are coupled with detection by uv. For the retinoids, fluorescent detection is possible and picogram quantities of retinol in plasma have been measured (58—62). These techniques are particularly powerful for the separation of isomers. Owing to the thermal lability of these compounds, gc methods have also been used but to a lesser extent. Recently, the utiUty of cool-on-column injection methods for these materials has been demonstrated (63). 

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Interestingly, carotenoids more abundant in the blood plasma than zeaxanthin, such as lycopene, P-carotene, and P-cryptoxanthin, do not accumulate in the retina. RPE cells express p,p-carotene 15,15 -monooxygenase (BCO), formerly known as P-carotene 15,l5 -dioxygcnase, an enzyme that catalyzes the oxidative cleavage of P-carotene into two molecules of all-trans-retinal (Aleman et al., 2001 Bhatti et al., 2003 Chichili et al., 2005 Leuenberger et al., 2001 Lindqvist and Andersson, 2002). Therefore it may be suggested that p -carotene transported into RPE-cells is efficiently cleaved into retinal molecules. BCO cleaves also P-cryptoxanthin (Lindqvist and Andersson, 2002), and its absence in the retina may also be explained by its efficient cleavage to retinoids. However, lycopene, often the most abundant carotenoid in human plasma, cannot serve as a substrate for BCO, and yet it is not detectable in the neural retina (Khachik et al., 2002). 

Gundersen and Blomhoff (1999) used online dilution with online SPE to measure vitamin A (retinol) and other active retinoids in animal plasma. The intention of online dilution in this application was on optimizing SPE extraction conditions rather than on peak focusing during analytical separation. An SPE cartridge packed with Bondapak C18 materials (37 to 53 jt/M, 300 A, Waters, Milford, Massachusetts) and a reversed-phase analytical column (250 x 2.1 mm inner diameter, Superlex pkb-100, Supelco, Bellefonte, Pennsylvania) were controlled by a six-port switching valve (Rheodyne, Cotati,... 

Unlike isotretinoin, acitretin (Soriatane) is not primarily sebosuppressive. Rather, it promotes normalization of dysregulated keratinocyte proliferative activity in the epidermis and is also antiinflammatory. Oral absorption is optimal when acitretin is taken with a fatty meal peak levels are reached approximately 3 hours after ingestion, while steady-state plasma levels are achieved after approximately 3 weeks of daily dosing. The mean terminal elimination half-life of the parent compound is 49 hours. However, when consumed with ethanol, acitretin may be transesterifled to form etretinate, a retinoid that is stored in adipose tissue, resulting in a much longer half-life (3-4 months or longer). 

For some agents for example valproic acid and ethanol, a threshold concentration must be reached before teratogenicity is induced and the effect is therefore related to the maximum plasma concentration For others such as retinoids and cyclophos-... 

Isotretinoin (Accutane) is a synthetic retinoid currently restricted to the oral treatment of severe cystic acne that is recalcitrant to standard therapies. The precise mechanism of action of isotretinoin in cystic acne is not known, although it appears to act by inhibiting sebaceous gland size and function. The drug is well absorbed, extensively bound to plasma albumin, and has an elimination half-life of 10-20 hours. 

Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25-50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years. 

FIGURE 12-40 General mechanism by which steroid and thyroid hormones, retinoids, and vitamin D regulate gene expression. The details of transcription and protein synthesis are discussed in Chapters 26 and 27. At least some steroids also act through plasma membrane receptors by a completely different mechanism. 

Water-insoluble hormones (steroid, retinoid, and thyroid hormones) readily pass through the plasma membrane of their target cells to reach their receptor proteins in the nucleus (Fig. 23-4). With this class of hormones, the hormone-receptor complex itself carries the message it interacts with DNA to alter the expression of specific genes, changing the enzyme complement of the cell and thereby changing cellular metabolism (see Fig. 12 10). 

Eukaryote organisms primarily respond to external signals by an initial signal perception by receptors. In general, such receptors can be either cytosolic or located on the plasma membrane [13-15]. The former mechanism applies to thyroid hormones (triiodothyronine and tetraiodothyronine or thyroxine), retinoids (e.g. retinoic acid), the insect developmental hormones such as ecdysone, steroid hormones (such as... 

Peng, Y.M., Peng, Y.S., Lin, Y., Moon, T., Roe, D.J., and Ritenbaugh, C.H. 1995. Concentrations and plasma-tissue-diet relationships of carotenoids, retinoids, and tocopherols in humans. Nutr. Cancer 23, 233-246. 

Another important field of application concerns food and beverages, especially wine, juices, and tea (A2, A11, A17, B4, K12, V7, Yl). The antioxidant components of food include vitamin E (a-tocopherol), vitamin A (retinoids), vitamin C (ascorbic acid), and also fi-carotene (provitamin A), other carotenoids (of which more than 600 compounds have been identified), flavonoids, simple phenols, and glucobrasicins (H3). Unfortunately, the TAC value of a food is not informative on the bioavailability of its antioxidants. It has been estimated that polyphenols are normally present in blood plasma at concentrations of 0.2-2 //M (PI). However, it has been demonstrated that feeding rats a quercetin-augmented diet can increase their plasma levels of quercetin and its metabolites up to 10-100 //M (M27), and transient increases in the concentration of plant-derived phenolic compounds can take place after ingestion of food and beverages, which may affect blood plasma TAC (see later). 

The FABPs are a family of carrier proteins for fatty acids and other lipophilic substances, such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Adipocyte fatty acid-binding protein (aP2 FABP4) is expressed in adipocytes and macrophages, and integrates inflammatory and metabolic responses. Studies in aP2-deflcient mice have shown that this lipid chaperone has a significant role in several aspects of the metabolic syndrome, including type 2 diabetes and atherosclerosis. FABP has also been introduced as a plasma marker of acute myocardial infarction. 

An example of gene expression can be illustrated by consideration of the action of steroid hormones, and in the control of sterol biosynthesis. Steroid hormones enter the cell by diffusion through the plasma membrane and bind to their steroid hormone receptor. These receptors are part of a large related family that includes those for glucocorticoids, oestrogens, androgens, thyroid hormone, calcitriol and the retinoids. All steroid hormone receptors are zinc finger transcription factors. The receptor must ... 

RETINOIDS-TRETINOIN CALCIUM CHANNEL BLOCKERS 1 plasma tretinoin levels and risk of 1 anti-tumour activity when coadministered with diltiazem, nifedipine or verapamil Due to induction of CYP3A4-mediated metabolism of tretinoin Avoid co-administration if possible... 

Anhydroretinol binds to plasma and intracellular RBPs, but not to the cellular retinoic acid binding proteins (CRABPs) or retinoid receptors. In experimental animals, it protects against the development of chemically induced tumors while showing none of the toxic effects of other retinoids. 

Oxoretinol is synthesized from canthaxin (see Figure 2.2) and occurs in plasma. It binds to the retinoic acid nuclear receptor (but not the RXR) and is active in tissue differentiation. In the early embryo, the main biologically active retinoid is 4-oxoretinaldehyde, which both activates RARs and also acts as a precursor of oxo-retinoic acid and oxoretinol. 

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