Am J Med Sci. 1989 Aug;298(2):83-8.  

19-Hydroxylase inhibition of adrenal mitochondrial P450 11
beta/18/19-hydroxylase by a suicide inhibitor.

Griffing GT, Holbrook M, Melby JC, Alberta J, Orme-Johnson NR.

Evans Memorial Department of Clinical Research, University Hospital, Boston,
Massachusetts 02118.

19-Nor-deoxycorticosterone (19-nor-DOC) is a mineralocorticoid that is increased
in some forms of experimental and human hypertension. The pivotal step in
19-nor-DOC biosynthesis is adrenal P450 19-hydroxylase, but this enzyme has not
been clearly distinguished from P450 11 beta/18-hydroxylase. This study
attempted to specifically inhibit adrenal 19-hydroxylation of
deoxycorticosterone (DOC) using a suicide aromatase inhibitor, 19-acetylenic
androstenedione (19-AA). Purified bovine P450 11 beta/18/19-hydroxylase was
incubated with excess substrate DOC, adrenodoxin, and adrenodoxin reductase in
the presence of increasing doses of the inhibitor, 19AA. 11 beta-, 18-, and
19-hydroxylation were measured by quantification of corticosterone, 18-OH-DOC,
and 19-OH-DOC respectively. Measurements of these products demonstrated that 11
beta- and 18-hydroxylation was not inhibited whereas 19-hydroxylation was
inhibited as manifested by decreased 19-OH-DOC formation (p less than .05). The
IC50 of 19-AA was approximately 10(-12) M. The specific inhibition of
19-hydroxylation suggests that the 19-hydroxylase may be an enzyme distinct from
the P450 11 beta/18-hydroxylase. This further suggests that 19-nor-DOC
biosynthesis may be under independent regulation and may be amendable to
specific in vivo inhibition.

PMID: 2788364 [PubMed - indexed for MEDLINE]