Characterization of the enzyme involved in the production of 19-nor-deoxycorticosterone in hamster

Abstract

19-Nor-corticosteroids are substances which have high mineralocorticoid activity and have been implicated in the development of essential hypertension. 19-Nor-deoxycorticosterone (19-nor-DOC) has been found in the urine of certain hypertensive patients suffering. However, very little is known regarding the origin and metabolism of 19-nor-DOC. Expression of the hamster adrenal cytochrome P450C11 cDNA in COS-1 cells has shown that this cytochrome has strong 19-hydroxylase activity, this activity being equivalent to that of 11beta-hydroxylase. Since one potential precursor of 19-nor-DOC is 19-hydroxy-deoxycorticosterone (19-OH-DOC), we have incubated this substrate in the presence of the hamster P450C11 expressed in COS-1 cells. We have found that the hamster P450C11 can transform 19-OH-DOC to 19-nor-DOC in high yield. These studies target, for the first time, the potential role of cytochrome P450C11 in the formation of 19-nor-DOC, a mineralocorticoid of adrenal origin that is possibly involved in the development of some types of hypertension.

Hypokalaemic paresis, hypertension, alkalosis and adrenal‐dependent hyperadrenocorticism in a dog

“…It is also possible that translocation of intracellular potassium associated with acidosis during the brief episode of illness at this time temporarily increased plasma potassium concentration, however blood gas measurements were not taken at this time. DOC, a possible contributor to hypokalaemia in this case, is increased by KTZ's inhibition of CYP11B1 24 (11β‐hydroxylase; Figure 4) but 19‐Nor‐DOC, a product of CYP11B1, decreases 25 . This may suggest a greater role for this metabolite of DOC in the pathogenesis of mineralocorticoid excess, as has been noted previously 2 .…”

“…DOC, a possible contributor to hypokalaemia in this case, is increased by KTZ's inhibition of CYP11B1 24 (11β-hydroxylase; Figure 4) but 19-Nor-DOC, a product of CYP11B1, decreases. 25 This may suggest a greater role for this metabolite of DOC in the pathogenesis of mineralocorticoid excess, as has been noted previously. 2 KTZ was discontinued due to clinical signs and laboratory abnormalities compatible with KTZ-induced hepatotoxicity.…”

New assumptions about oxidative processes involved in steroid hormone biosynthesis: Is the role of cytochrome P-450-activated dioxygen limited to hydroxylation reactions or are dioxygen insertion reactions also possible?

“…In vitro results may apply only to those events occurring in the incubation flask. This limitation may also be applicable when the process being studied is contained in isolated tissue slices; or in transfected Cos-1 cells [47,48]. Even in such experiments, the investigator decides which substrate to use.…”

“…In addition they found that cells transfected with plasmids containing P-450 aldo cDNA converted DOC into corticosterone, aldosterone, 18-hydroxycorticosterone, 18-hydroxy DOC and 19-hydroxy DOC. In 1998 Courtemanche and LeHoux [48] showed that, when used as a substrate for 11␤-hydroxylase, 19-hydroxydeoxycorticosterone was converted to 19-nordeoxycorticosterone, a very potent mineralocorticoid.…”