Vitamin A and Retinoid Metabolism in Human Liver
Introduction
Retinoids are a group of chemical compounds that are chemically related to vitamin A. Retinol, as an important endogenous retinoid, however, is devoid of biological activity. Retinoic acid (RA), the biologically active metabolite of vitamin A (retinol), mediates the functions of vitamin A required for growth and development. Retinoic acid can regulate transcription and expression of hundreds of genes through binding to retinoic acid receptors (RARalpha;, RARbeta;, and RARgamma;) and peroxisome proliferator-activated receptor (PPAR)beta;/delta; (Blomhoff and Blomhoff, 2006), regulating multiple biological processes associated with vision, skin, nervous system, reproduction, spermatogenesis, stem cell differentiation, regulation of glucose homeostasis, cell cycle and apoptosis. RA is believed to exist in vivo as at least five isomers, including: all-trans retinoic acid (atRA), 9-cis-RA, 11-cis-RA, 13-cis-RA, and 9,13-di-cis-RA(Thatcher and Isoherranen, 2008). Among these, atRA is believed to be the most active isomer due to its relatively high concentration in vivo and its high potency in binding to RARs (Tang and Gudas, 2011).
Aside being important endogenous compounds, RA isomers are also used in the treatment of a number of dermatological conditions such as inflammatory skin disorders, skin cancers, psoriasis and skin wrinkles (Kafi et al., 2007). AtRA has been proved to induce complete remission (CR) in patients with low-to-intermediate-risk acute promyelocytic leukemia (APL)(Lo-Coco et al., 2013). The underlying mechanism is that atRA can lead to the degradation PML-RARA fusion protein, which further results in the elimination of APL-initiating cells(Iland et al., 2012). 13-cis-RA is used for the treatment of acne and in children with neuroblastoma (Veal et al., 2007). 9-cis-RA has been used to treat severe chronic hand eczema (Schmitt-Hoffmann et al., 2011).
The liver is the major storage organ for retinoid in the body (Shirakami et al., 2012). Two main cells are closely related to retinoid metabolism in liver, which are hepatocytes and hepatic stellate cells (HSCs). Hepatocytes play a critical role in the uptake and processing of dietary retinoid into the liver, and in the synthesis of retinol binding protein (RBP). HSCs are the major cellular site for retinoid storage in animals, accounting for approximately 50–60% of the total retinoid present in the entire body, and 70–90% of all retinoid in the liver(Shirakami et al., 2012).
The major source of retinoid from the diet are plant pigments such as beta;-carotene and retinyl esters (RE) and retinol derived from animal sources(Tang and Gudas, 2011). RE from food are hydrolyzed by retinyl ester hydrolases (REHs) to retinol, which can be absorbed in intestine and then be converted back to RE under the catalysis of lecithin retinol acyltransferase (LRAT). Vitamin A is stored mainly in liver as the form of retinyl esters (RE). Retinol is the circulating form and a precursor form, which is enzymatically activated to retinoic acid (RA) via a two-step sequential oxidation synthesis. Retinol is first oxidized to retinal by alcohol dehydrogenase (ADHs) and retinol dehydrogenase (RDHs), and then converted into atRA by retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2, and ALDH1A3) . This step is irreversible, which means once RA is produced, it cannot be reduced back to retinol. AtRA can be further metabolized into more polar metabolites (Blomhoff and Blomhoff, 2006). Even though,ALDH1As are believed to be main enzymes catalyzing atRA biosynthesis, it has been shown that are also capable of converting RAL to atRA. However, the relative contribution made by these enzymes in atRA biosynthesis is not completely understood.
Aldehyde dehydrogenases(ALDH) are a group of NAD(P) -dependent enzymes that catalyze the oxidation of a wide variety of endogenous and exogenous aldehydes into carboxylic acids(Marchitti et al., 2009). These enzymes are found in many tissues of the body but are of highest concentration in the liver. The active site of ALDH binds to one molecule of an aldehyde and an NAD(P) that functions as a cofactor.
Aldehyde oxidase (AOX) is a metabolizing enzyme with wide substrate specificity. It can catalyze the oxidation of aromatic and aliphatic aldehydes into carboxylic acids, and also catalyze the hydroxylation of some heterocyclic compounds(Terao et al., 2016). It is also capable of catalyze the oxidation of cytochrome P450 (CYP450) intermediate products. AOX has a significant impact on the metabolism of many drugs. AOX greatly contributes to the hepatic clearance of drugs and other compounds, because of its broad substrate specificity. Rodents, such as mice and rats, are characterized by the largest number of AOXs, synthesizing the so called AOX1, AOX2, AOX3, and AOX4 isoenzymes. In contrast, humans and the majority of primates produce a single AOX isoform, i.e., the orthologue of mouse AOX1(Terao et al., 2016). Along with CYP450, cytoplasmic AOX1 is the major enzyme involved in the hepatic phase I metabolism of numerous xenobiotics.
WIN 18,446 is a potent reversible inhibitor of ALDH1A1 and ALDH1A3 enzymes (IC50 values 102 plusmn; 2 nM and 187 plusmn; 1 nM) and a time dependent inhibitor of ALDH1A2 (kinact = 22.0 plusmn; 2.4 h-1, KI = 1,026 plusmn; 374 nM) (Arnold et al., 2015). The administration of the WIN 18,446 was previously proved to potently inhibit spermatogenesis in rabbits by inhibiting retinoic acid synthesis (Paik et al., 2014).
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