il\VOLVEMENT OF RETII\OIC ACID II{ - MSpace at the University of ...

IV.b.s. Retinoic acid catabolism: Catabolism of retinoic acid is achieved through a
phase I and phase II metabolism (Marill et al. 2003). In a phase I metabolism retinoic
acid is oxidized, depending on the tissue t1pe, through at least two pathways: a major and
a minor pathway (Pijnappel et al. 1993). A phase I major pathway represents a preferred
route of catabolism and is charactenzed by the 4-hydroxylation of retinoic acid, which
produces 4-OH-RA. 4-OH-RA is further dehydrogenated to form 4-oxo retinoic acid'
Contrastly, a phase I minor pathway is characterizedby the 18-hydroxylation of retinoic
acid, which results in the production of 18-OH-RA. After the metabolic conversion, most
of the RA metabolites remain bound to CRABP and some of them such as 4-bxo-RA are
shown to bind to RXR B (Pijnappel et al. 1gg3). The main enzymes involved in the phase
I metabolism of retinoic acid are cytochrome P450 family members including
c\?2c8,cYP 3A7, IAl,}Cg,1A2,3^4 and cYP 26 (Chen et al. 2000a; Leo et al' 1989;
Marill et al. 2000; Mcsorley and Daly 2000; Nadin and Murray 1999). Retinoic acid is
also capable of the autoregulation of its own metabolism. It is documented that ItA,
through its binding to both RAR and RXR receptors, will regulate the expression of CYP
26 enzymes in a number of cell models. (Marill el aL.2003). Phase II metabolism of
retinoic acid is mediated through the processes of conjugation. This is achieved by the
glucuronidation of retinoic acid and its polar metabolites. (Czemik et al. 2000)' After
glucorinidation, retinoic acid metabolites are excreted through the bile route in a form of
all-trans-retinoyl B glucuronide (Blaner V/S and Olson JA 1994).
IV.c.l.Introduction: Retinoic acid is involved in the regulation of a number of essential
biological processes such as homeostasis, growth, development and differentiation' This
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