CDNA CLONING OF HUMAN RETINOIC ACID-METABOLIZING ENZYME (HP450RAI) IDENTIFIES A NOVEL FAMILY OF CYTOCHROMES P450 (CYP26)

Retinoids, including all-trans retinoic acid (RA) and its stereoisomer 9-cis-RA play important roles in regulating gene expression, through interactions with nuclear receptors, during embryonic development and in the maintenance of adult epithelial tissues (Chambon, P. (1995) Rec . Prog. Horm. Res. 50, 317-32; Mangelsdorf, D. J., and Evans, R. M. (1 995) Cell 83, 841-850; Petkovich, M. (1992) Annu. Rev. Nutr. 12, 443-4 71). Evidence suggests that 4-hydroxylation of RA inside the target ce ll limits its biological activity and initiates a degradative process of RA leading to its eventual elimination. However, 18-hydroxylation a nd glucuronidation may also be important steps in this process. In thi s paper, we describe the cloning and characterization of the first mam malian retinoic acid-inducible retinoic acid-metabolizing cytochrome P 450 (hP450RAI), which belongs to a novel class of cytochromes (CYP26). We demonstrate that hP450RAI is responsible for generation of several hydroxylated forms of RA, including 4-OH-RA, 4-oxo-RA, and 18-OH-RA. We also show that hP450RAI mRNA expression is highly induced by RA in certain human tumor cell lines and further show that RA-inducible RA m etabolism may correlate with P450RAI expression. We conclude that this enzyme plays a key role in RA metabolism, functioning in a feedback l oop where RA levels are controlled in an autoregulatory manner.