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Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1.
[primary hyperoxaluria type 1]
Primary
hyperoxaluria
type
1
(
PH
1
)
is
a
rare
hereditary
calcium
oxalate
kidney
stone
disease
caused
by
a
deficiency
of
the
liver
-
specific
pyridoxal-phosphate-dependent
peroxisomal
enzyme
alanine
:
glyoxylate
aminotransferase
(
AGT
)
.
About
one
third
of
patients
are
responsive
to
pharmacological
doses
of
pyridoxine
(
vitamin
B
6
)
,
but
its
mechanism
of
action
is
unknown
.
Using
stably
transformed
Chinese
Hamster
Ovary
(
CHO
)
cells
expressing
various
normal
and
mutant
forms
of
AGT
,
we
have
shown
that
pyridoxine
increases
the
net
expression
,
catalytic
activity
and
peroxisomal
import
of
the
most
common
mistargeted
mutant
form
of
AGT
(
i
.
e
.
Gly
170
Arg
on
the
background
of
the
polymorphic
minor
allele
)
.
These
multiple
effects
explain
for
the
first
time
the
action
of
pyridoxine
in
the
most
common
group
of
responsive
patients
.
Partial
effects
of
pyridoxine
were
also
observed
for
two
other
common
AGT
mutants
on
the
minor
allele
(
i
.
e
.
Phe
152
Ile
and
Ile
244
Thr
)
but
not
for
the
minor
allele
mutant
AGT
containing
a
Gly
41
A
rg
replacement
.
These
findings
demonstrate
that
pyridoxine
,
which
is
metabolised
to
pyridoxal
phosphate
,
the
essential
cofactor
of
AGT
,
achieves
its
effects
both
as
a
prosthetic
group
(
increasing
enzyme
catalytic
activity
)
and
a
chemical
chaperone
(
increasing
peroxisome
targeting
and
net
expression
)
.
This
new
understanding
should
aid
the
development
of
pharmacological
treatments
that
attempt
to
enhance
efficacy
of
pyridoxine
in
PH
1
,
as
well
as
encouraging
a
re
-evaluation
of
the
extent
of
pyridoxine
responsiveness
in
PH
1
,
as
more
patients
than
previously
thought
might
benefit
from
such
treatment
.
Diseases
Validation
Diseases presenting
"partial effects of pyridoxine"
symptom
primary hyperoxaluria type 1
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