AtRA Catabolism

atRA induces its own metabolism via cytochrome P450 (CYP) into a variety of initial catabolites, including 5,6-epoxy-atRA, 18-hydroxy-atRA, and 4-hydroxy-atRA. Metabolism of atRA limits its activity; conversely, inhibitors of atRA metabolism enhance atRA potency. CYP26A1 may catalyze the major degree of atRA catabolism, as evidenced by null mice dying in mid- to late gestation with serious morphological defects. Two other P450's, CYP26B1 and CYP26C1, also catabolize atRA, but null mice have not been reported. Several other CYPs reportedly catabolize atRA, but these candidates (CYP1A1/2, CYP2A6, CYP2C8/9, CYP2E1, and CYPP3A4/5) are not induced by atRA—in contrast to the well-established ability of atRA to induce its own metabolism as well as CYP26A1 transcrip-tion—and most have inefficient kinetics in vitro with atRA.

Presenting atRA to microsomes bound with CRABP(I) enhances kinetic efficiency of catabolism sevenfold. There seems to be little doubt that CRABP(I) sequesters atRA: Delivering the sequestered atRA for efficient catabolism seems to be a logical mechanism to discharge the ligand without releasing it back into the cell. Unfortunately, this insight does not reveal the primary purpose for CRABP(I) impounding atRA in the first place.

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