Delivery of retinoid-based therapies to target tissues

Abstract

Through its various metabolites, vitamin A controls essential physiological functions. Both naturally occurring metabolites and novel retinoid analogues have shown effectiveness in many clinical settings that include skin diseases and cancer, and in animal models of human conditions affecting vision. In this review, we analyze several potential retinoid-based therapies from the point of view of drug metabolism and transport to target tissues. We focus on the endogenous factors that affect the absorption, transport, and metabolism of retinoids by taking into account data obtained from the analysis of animal models that lack the enzymes or proteins involved in the storage and absorption of retinoids. We also discuss findings of toxicity associated with retinoids in an effort to improve the outcome of retinoid-based therapies. In this context, we review evidence that esterification of retinol and retinol-based drugs within target tissues provides one of the most efficient means to improve the absorption and to reduce the toxicity associated with pharmacological doses of retinoids. Future retinoid-based therapeutic strategies could involve targeted delivery mechanisms leading to lower toxicity and improved effectiveness of retinoids.

Figure 1

Retinoid metabolism and bioactive retinoids in higher vertebrates. Known endogenous bioactive retinoids are highlighted by yellow boxes and include all-trans-retinoic acid (RA), which regulates gene expression via RAR, 11-cis-retinal, which is the chromophore of the photoreceptor molecule rhodopsin, all-trans-13,14-dihydroxyretinol, and the retro-retinoids, AR and 14-hydroxy-retro-retinol, which control cellular proliferation. All-trans-retinol can be esterified by the LRAT or by the ARAT enzyme to produce retinyl esters that can be hydrolyzed back to all-trans-retinol by retinyl ester hydrolase (REH) (reaction 1). The LRAT enzyme uses phospholipid (PL) as acyl donors and prefers retinol complexed to CRBP as the substrate. The oxidation of all-trans-retinol by short chain dehydrogenase/reductase (SDR) or ADH enzymes leads to the formation of all-trans-retinal (reaction 2), which in turn is oxidized by retinaldehyde dehydrogenases (RALDH) to all-trans-RA (reaction 3). All-trans-RA can be converted to more polar metabolites through oxidation by cytochrome P450 CYP26 enzymes (reaction 4) or through glucuronidation by UDP-glucuronosyltransferase (UGT) enzymes (reaction 5). All-trans-retinol can be saturated by RetSat and leads to the formation of all-trans-13,14-dihydroretinol (reaction 6), which can be oxidized by the same enzymes as those of all-trans-retinol to produce all-trans-13,14-dihydroretinoic acid. The production of 11-cis-retinal occurs in RPE cells and through esterification, isomerization, and oxidation reactions, with isomerization involving the RPE65 enzyme (reaction 7). An alternate pathway for the production of the visual chromophore for cones operates independently of RPE65 (reaction 8). The enzymes involved in the production of all-trans-13,14-dihydroxyretinol, AR, and 14-hydroxy-retro-retinol in vertebrates are not currently known, though a retinol dehydratase from insects was shown to catalyze the formation of AR.

Figure 2

Targets of retinoid treatments. Both all-trans-retinol and all-trans-retinyl esters (palmitate) are effective in the treatment and prevention of vitamin A deficiency (VAD). The reconstitution of rhodopsin with 9-cis-retinal forms isorhodopsin and is an effective means of restoring visual function in several models of Leber congenital amaurosis (LCA). Inhibitors of the visual cycle, retinylamine and 13-cis-RA, can slow the rate of 11-cis-retinal formation in cases where excessive activation of rhodopsin can lead to phototoxicity and accumulation of all-trans-retinal and toxic metabolites as seen in Stargardt disease and age-related macular degeneration. A similar result can also be obtained with N-(4-hydroxyphenyl)retinamide (4-HPR or fenretinide), which binds RBP and leads to its excretion through glomerular filtration. Retinylamine can be amidated by the LRAT enzyme, allowing for the storage of the drug in an inactive form with lower toxicity. Independently of RAR, 4-HPR can lead to the apoptosis of tumor cells. RAR can be modulated by all-trans-RA, 9-cis-RA, and many synthetic agonists and antagonists. The retinoid X receptor can be modulated by 9-cis-RA and several synthetic agonists and antagonists. Both 13-cis- and 9-cis-RA can isomerize to all-trans-RA in vivo. The drug targets are shown in bold font, and the retinoids used in various therapies are shown in red font.