Retinoid, endogenous

Figure 5.2 Schematic representation of the final column-switching system (a) foi ward-flush position (b) back-flush position (further details are given in the text). Reprinted from Journal of Chromatography, A 828, A. K. Sakhi et al. Quantitative determination of endogenous retinoids in mouse embiyos by high-performance liquid cliromatography with on-line solid-phase exti action, column switcliing and electi ochemical detection , pp. 451 -460, copyright 1998, with permission from Elsevier Science.

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. 

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

RH above can represent a very wide variety of xenobi-otics, including drugs, carcinogens, pesticides, petroleum products, and pollutants (such as a mixture of PCBs). In addition, endogenous compounds, such as certain steroids, eicosanoids, fatty acids, and retinoids, are also substrates. The substrates are generally lipophilic and are rendered more hydrophilic by hydroxy-lation. 

McGowan, S. E., Doro, M. M., and Jackson, S. (1997). Endogenous retinoids increase perinatal elastin gene expression in rat lung fibroblasts and fetal explants. Am. J. Physiol. 273, L410-L416. 

Alitretinoin (Panretin) is a naturally occurring endogenous retinoid that binds to and activates all known retinoid receptors (both RARs and RXRs). It is approved for the topical treatment of cutaneous lesions of Kaposi s sarcoma. Most patients have local irritation while using alitretinoin gel however, the irritation rarely necessitates discontinuation of therapy. 

A. K. Sakhi, T. E. Gundersen, S. M. Ulven, R. Blomhoff and E. Lundanes, Quantitative determination of endogenous retinoids in mouse embryos by high-performance liquid chromatography with on-line solid-phase extraction, column switching and electrochemical detection , J. Chromatogr. 828 451-460 (1998). 

Like other nuclear receptors (e.g., steroid hormone receptors, thyroid hormone receptors) the PPARs function as ligand-activated transcription factors. As illustrated in Fig. 1 (see color insert) individual PPARs function as dimers with members of the retinoid X receptor (RXR) family (23). Evidence for an interaction of PPARs with RXRs includes co-expression studies that were performed with yeast lacking endogenous nuclear receptors (24). 

There are many endogenous substrates, of widely different chemical structure, that are metabolized through oxidative, peroxidative, and reductive changes introduced by P450 enzymes. These include saturated and unsaturated fatty acids, eicosanoids, sterols and steroids, bile acids, vitamin D derivatives, retinoids, and uroporphyrinogens (Tables 9.4 and 9.5). 

CYP1B1 is also expressed in the fetus in multiple tissues, particularly in thymus, spleen, kidney, and adrenal. A null CYP1B1 phenotype in humans has been associated with appearance of primary congenital glaucoma. Consistent with an important endogenous role for this enzyme in development of the eye, CYP1B1—which, in addition to biotransformation of xenobiotics, is also capable of metabolizing retinoid and sex steroids—is expressed in embryonic ocular tissues. 

The ligand binding pocket of USP is filled by a fortuitous phospholipid co-purified and co-crystallized with the USP LBD that was fiirther characterized by mass-spectroscopic and chemical analysis [57]. In a similar way, recent crystallographic investigations of the retinoid-acid related orphan receptor (3 (ROR (3) [58] and of the heterodimeric complex RARa/RXRa [30] revealed an E.coli endogeneous fatty acid in the ROR (3 and in the RXRa subunit, respectively. 

Alltretinoln. Alitretinoin. 9-ci.s-reiinoic acid (Panretin). is a yellow powder that is slightly. soluble in ethanol and insoluble in water. Alitretinoin is a naturally occurring endogenous retinoid. 

Adapalene is a naphthoic acid derivative, thus differing markedly from the endogenous retinoids. This rc.sults in different ability to bind the many retinoic acid-binding proteins. It binds with RARs but not RXRs or CRABPs." ... 

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. 

Retinoic acid, an endogenous retinoid, is an oxidized metabolite of retinol (vitamin A), and the most potent known inducer of differentiation in vitro (17-191. It is, therefore, most likely the form of vitamin A which promotes normal cellular differentiation. Because cancer is fundamentally a loss of cellular differentiation, physiological concentrations of retinoic acid may play an important role in the etiology of cancer. 

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