19‐Hydroxylase Inhibition of Adrenal Mitochondrial P450 11/18/19‐Hydroxylase by a Suicide Inhibitor
作者:
GEORGE GRIFFING,
MONIKA HOLBROOK,
JAMES MELBY,
JOHN ALBERTA,
NANETTE ORME-JOHNSON,
期刊:
The American Journal of the Medical Sciences
(OVID Available online 1989)
卷期:
Volume 298,
issue 2
页码: 83-88
ISSN:0002-9629
年代: 1989
出版商: OVID
关键词: 19-Hydroxylase;11β-Hydroxylase;18-Hydroxylase;19-OH-DOC;18-OH-DOC;Corticosterone;Adrenal P450 Steroid Hydroxylases;19-Acetlyenic Androstenedione;Adrenodoxin;Adrenodoxin Reductase
数据来源: OVID
摘要:
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 11β/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 11β/18/19-hydroxylase was incubated with excess substrate DOC, adrenodoxin, and adrenodoxin reductase in the presence of increasing doses of the inhibitor, 19AA. 11β-, 18-, and 19-hydroxylation were measured by quantification of corticosterone, 18-OH-DOC, and 19-OH-DOC respectively. Measurements of these products demonstrated that 11β- and 18-hydroxylation was not inhibited whereas 19-hydroxylation was inhibited as manifested by decreased 19-OH-DOC formation (p <.05). The IC50 of 19-AA was approximately 10-12M. The specific inhibition of 19-hydroxylation suggests that the 19-hydroxylase may be an enzyme distinct from the P450 11β/18-hydroxylase. This further suggests that 19-nor-DOC biosynthesis may be under independent regulation and may be amenable to specific in vivo inhibition.
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