ROLE OF STEROID 11-BETA-HYDROXYLASE AND STEROID 18-HYDROXYLASE IN THE BIOSYNTHESIS OF GLUCOCORTICOIDS AND MINERALOCORTICOIDS IN HUMANS

A gene encoding steroid 18-hydroxylase (P-450C18) was isolated from a human genomic DNA library. It was identified as CYP11B2, which was previously postulated to be a pseudogene or a less active gene closely related to CYP11B1, the gene encoding steroid 11-beta-hydroxylase (P-450(11beta)) [Mornet, E., Dupont, J., Vitek, A. & White, P. C. (1989) J. Biol. Chem. 264, 20961-20967]. The nucleotide sequence of the promoter region of the P-450C18 gene is strikingly different from that of the P-450(11-beta) gene, although the sequences of their exons are 93 % identical. The transient expression in Y-1 adrenal tumor cells of CAT constructs with a series of deletion mutants of promoter regions of both genes indicated that the two genes are regulated differently. P-450C18 as expressed in COS-7 cells exhibits steroid 18-hydroxylase activity to catalyze the synthesis of aldosterone and 18-oxocortisol and exhibits steroid 11-beta-hydroxylase activity as well. In contrast, P-450(11-beta) as expressed in the cultured cells exhibits steroid 11-beta-hydroxylase activity exclusively but fails to catalyze the synthesis of aldosterone and 18-oxocortisol. These results indicate that P-450(11-beta) and P-450C18 are products of two different genes and that the former participates in the synthesis of glucocorticoids whereas the latter participates in the synthesis of mineralocorticoids in humans.