Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=21070833
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\21070833
.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Mol+Cell+Endocrinol
2011 ; 336
(1-2
): 174-9
Nephropedia Template TP
gab.com Text
Twit Text FOAVip
Twit Text #
English Wikipedia
Consequences of POR mutations and polymorphisms
#MMPMID21070833
Miller WL
; Agrawal V
; Sandee D
; Tee MK
; Huang N
; Choi JH
; Morrissey K
; Giacomini KM
Mol Cell Endocrinol
2011[Apr]; 336
(1-2
): 174-9
PMID21070833
show ga
P450 oxidoreductase (POR) transports electrons from NADPH to all microsomal
cytochrome P450 enzymes, including steroidogenic P450c17, P450c21 and P450aro.
Severe POR mutations A287P (in Europeans) and R457H (in Japanese) cause the
Antley-Bixler skeletal malformation syndrome (ABS) plus impaired steroidogenesis
(causing genital anomalies), but the basis of ABS is unclear. We have
characterized the activities of ?40 POR variants, showing that assays based on
P450c17 activities, but not cytochrome c assays, correlate with the clinical
phenotype. The human POR gene is highly polymorphic: the A503V sequence variant,
which decreases P450c17 activities to ?60%, is found on ?28% of human alleles. A
promoter polymorphism (?8% of Asians and ?13% of Caucasians) at -152 reduces
transcriptional activity by half. Screening of 35 POR variants showed that most
mutants lacking activity with P450c17 or cytochrome c also lacked activity to
support CYP1A2 and CYP2C19 metabolism of EOMCC (a fluorogenic non-drug
substrate), although there were some remarkable differences: Q153R causes ABS and
has ?30% of wild-type activity with P450c17 but had 144% of WT activity with
CYP1A2 and 284% with CYP2C19. The effects of POR variants on CYP3A4, which
metabolizes nearly 50% of clinically used drugs, was examined with multiple,
clinically relevant drug substrates, showing that A287P and R457H dramatically
reduce drug metabolism, and that A503V variably impairs drug metabolism. The
degree of activity can vary with the drug substrate assayed, as the drugs can
influence the conformation of the P450. POR is probably an important contributor
to genetic variation in both steroidogenesis and drug metabolism.
free
free
free
