Identification of the human cytochrome P450, P450RAI-2, which is predominantly expressed in the adult cerebellum and is responsible for all-trans-retinoic acid metabolism.
Retinoids, particularly all-trans-retinoic acid (RA), are potent regulators of cell differentiation, cell proliferation, and apoptosis. The role of all-trans-RA during development and in the maintenance of adult tissues has been well established. The control of all-trans-RA levels in cells and tissues is regulated by the balance between its biosynthesis and its catabolism to inactive metabolites. The cytochrome P450 enzyme P450RAI (herein renamed P450RAI-1) is partially responsible for this inactivation of all-trans-RA. In this report, we describe the identification, molecular cloning, and characterization of a second related enzyme, P450RAI-2, which is also involved in the specific inactivation of all-trans-RA. Transiently transfected P450RAI-2 can convert all-trans-RA to more polar metabolites including 4-oxo-, 4-OH-, and 18-OH-all-trans-RA. Competition experiments with other retinoids suggest that all-trans-RA is the preferred substrate. The high level of expression of P450RAI-2, particularly in the cerebellum and pons of human adult brain, suggests a unique role for this enzyme in the protection of specific tissues from exposure to retinoids.
White
J A
JA
Cytochroma Incorporated, Biosciences Complex, 116 Barrie Street, and Department of Biochemistry, Medicine, Queen's University, Kingston, ON, K7L 3N6, Canada.
Ramshaw
H
H
Taimi
M
M
Stangle
W
W
Zhang
A
A
Everingham
S
S
Creighton
S
S
Tam
S P
SP
Jones
G
G
Petkovich
M
M
D000595:Amino Acid Sequence; D001483:Base Sequence; D002478:Cells, Cultured; D002531:Cerebellum / Q000201:enzymology*; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D000072516:Retinoic Acid 4-Hydroxylase; D013379:Substrate Specificity; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000072516:Retinoic Acid 4-Hydroxylase