RETINOID METABOLISM AND BINDING PROTEINS

13 May

The metabolic fate of retinoids is controlled by two classes  of intracellular binding proteins: the cellular  retinol binding protein type I (CRBP I) and the cellular  retinoic acid  binding protein type  II (CRABP II) (17,18). These  sequester the  retinoids, so that  it is only  available for reaction with  specific  enzymes. The holo-CRBP  retinol complex can  serve  as a substrate for lecithin  retinol  acyl transferase (LRAT) (19) when the retinoid status is high,  conversely when low, it serves  as a substrate for retinol   dehydrogenase  synthesizing retinal, which   ultimately gets  converted to all-trans-RA  (Fig. 4). The transport into the nucleus and  further metabolism of all- trans-RA  is controlled by CRBP I and  CRABP II. It is suggested that  CRBP I trans- port all-trans-RA  into the nucleus, whereas CRABP II sequesters excess all-trans-RA in the cytoplasm facilitating its degradation. Metabolic  inactivation of all-trans-RA to 4-hydroxyretinoic acid  occurs  via  a cytochrome P450 enzyme (CYP26; Fig. 4) (20,21). This hydroxylase activity  is actually induced in vivo by RA in human epi- dermis but  can  be inhibited by azoles.  In the  presence of low-dose RA or ROH, azoles  amplify the  human skin  responses to retinoids in a manner characteristic

FIGURE 4    Schematic representation of retinol metabolism. Abbreviations: CRABP, cellular retinoic acid binding protein; LRAT, lecithin retinol acyl transferase; RA, retinoic acid; RAL, retinal; RE, retinyl ester; ROL, retinol.

of the retinoids at a higher dose  (22). These  agents have  been  called  retinoic  acid metabolism breakdown agents (RAMBAs)  or retinomimetics. Azoles  also  inhibit the   RA-induced  expression  of  cytochrome  24-hydroxylase,  which   inactivates

1,25-dihydroxyvitamin  D3.

In  human  keratinocytes, all-trans-RA   regulates its  own  biosynthesis from atROH  through the regulation of retinol  esterification and,  as such,  RAMBA-type agents are not optimal (23). Treatment with  all-trans-RA  induces retinol-esterifying activity   in  proliferating  keratinocytes. LRAT was  induced by  all-trans-RA   and reduces the  conversion of ROH  to RA, resulting in sequestration of ROH  in REs. Acyl retinol  acyl transferase activity  is also present. Several  other  enzymatic steps have   been   identified,  which   if  manipulated  can   deliver  improved  retinoid responses (24).

EFFECTS OF RETINOIDS

Hypovitaminosis has been related to the expression of acne (25), and so its addition to skin should alleviate the condition. All-trans-RA was the first retinoid used,  but it was ineffectual on acne when used  systemically. 13-cis-RA (isotretinoin), however, is an extremely effective  oral  anti-acne drug by causing marked sebosuppression (26). 13-cis-RA has been shown to inhibit  significantly sebocyte proliferation, differ- entiation, and lipid  synthesis in vivo. Despite its potent biological  effects, 13-cis-RA exhibits   only  low-binding affinity  for  CRABP  and  nuclear receptors (27).  This unique antisebotrophic activity  results from  a selective  isomerization to all-trans- RA intracellularly in sebocytes, reduces all-trans-RA  inactivation compared with all-trans-RA,  and  mediates inhibition of sebocyte  proliferation (28). The synthesis of CRABP II, which  facilitates the  degradation of intracellular all-trans-RA,  was delayed and  induced lesser  by  13-cis-RA when compared with  all-trans-RA,  in vitro. Although all-trans-RA in trace amounts promotes sebocyte growth and differ- entiation,  larger   doses   induce  atrophy  of  the   sebaceous  gland  and   decrease

sebogenesis. In vitro all-trans-RA  and selective  RAR agonists increase lipid-forming colonies  except at higher doses  (1026  M), in which  only a small number of colonies grew  but  they  were  differentiated more  greatly.  On the other  hand, RXR agonists increased the cell growth slightly  and  lipid-forming colonies  dramatically (29 – 31).

It is important to remember that RA effects in vitro may be completely differ- ent to in vivo. Retinoic acid induces sebocyte differentiation in preputial sebocytes, yet in in vivo  the  opposite occurs.  Equally,  the  effects  of RA on the  keratinocyte differentiation process  are  contradictory in  vitro  and  in  vivo.  Nevertheless, the effects of retinoids on epidermal differentiation will help  to improve the acnegen- esis  state.   Increased  levels   of  epidermal  transglutaminase  and   involucrin are observed together with  increases in K6, as would be expected for a proliferating epidermis, but the differentiation in keratin markers (K1 and K10) are not inhibited in vivo.  A unique keratin, K13 is also  induced in vivo.  Filaggrin and  loricrin  are increased in  the  longer   term  (four  months) application of  RA.  As  it  has  been recently reported that  reduced Langerhans cell  (LC) activity  decreases in  acne, the increases in LC activity  by RA will also be beneficial  (32).

The mechanism of action  of isotretinoin has however remained elusive,  as it does  not bind  itself to the retinoid receptors. Multiple actions  have  been proposed from inhibition of sebaceous gland  activity, inhibition of the growth of P. acnes, inhi- bition  of inflammation, and  improvements in follicular epithelial differentiation. More  recently, it has  been  shown that  isotretinoin competitively inhibits 3 alpha- hydroxysteroid oxidation by retinol dehydrogenase, resulting in reduced formation of  dhihydrotestosterone  and   thereby  reduced  sebogenesis (33).  Retinoids are reported to increase the expression of transforming growth factor (TGF beta 1 – 3), and  these  inhibit  keratinocyte proliferation. However, TGF beta-2  and  3, but  not TGF beta-1,  reduce cell proliferation and  lipogenesis in human sebaceous glands in organ  culture studies, suggesting that  these  growth factors  may  also contribute to the effects of retinoids on sebaceous glands (34 – 37).

At  present, Accutane (oral  13-cis-RA) is available for  the  oral  treatment  of acne,   whereas  topical   treatments  include  Retin-A   (micronized  all-trans-RA)— Differin  (adapalene or CD271). Retinoic  acid  cannot  be used  in cosmetic  products but  retinol  can (Fig. 5) (36). This does  have  some  efficacy, but  several  new  routes are  being  proposed to enhance its activity  by inhibiting esterification and  degra- dation enzymes and  also manipulation of HDAC  activities (37).

FIGURE 5    Typical structures of retinoids.  Abbreviation:  RA, retinoic acid.

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