Abstract: Arsenic alters the function of glucocorticoid receptor as a transcription factor

Nation­al Library of Med­i­cine MEDLINE Database

TITL: Arsenic alters the func­tion of the glu­co­cor­ti­coid recep­tor as a tran­scrip­tion factor.

AUTH: Kaltrei­der RC; Davis AM; Lar­iv­iere JP; Hamil­ton JW

ORGA: Depart­ment of Phar­ma­col­o­gy and Tox­i­col­o­gy, Dart­mouth Med­ical School,
Hanover, NH 03755–3835, USA.

PUB TYPE: Jour­nal Article.

CITE: Envi­ron­men­tal Health Per­spec­tives 2001 Mar; 109 (3): 245–51

LANG: ENG; English

ABST: Chron­ic human expo­sure to nonovert­ly tox­ic dos­es of arsenic is associated
with an increased risk of can­cer. Although its car­cino­genic mech­a­nism is still
unknown, arsenic does not direct­ly cause DNA dam­age or muta­tions and is
there­fore thought to act prin­ci­pal­ly as a co-muta­gen, co-car­cino­gen, and/or
tumor pro­mot­er. Pre­vi­ous stud­ies in our lab­o­ra­to­ry demon­strat­ed that effects of
low-dose arsenic (III) (arsen­ite) on expres­sion of the hormone-regulated
phos­pho­enolpyru­vate car­boxyk­i­nase (PEPCK) gene were strong­ly asso­ci­at­ed with the
glu­co­cor­ti­coid recep­tor (GR)-mediated reg­u­la­to­ry path­way. We there­fore examined
specif­i­cal­ly the effects of arsen­ite on the bio­chem­i­cal func­tion of GR in
hor­mone-respon­sive H4IIE rat hepatoma cells. Com­plete­ly non­cy­to­tox­ic arsenite
treat­ments (0.3–3.3 microM) sig­nif­i­cant­ly decreased dexamethasone-induced
expres­sion of tran­sient­ly trans­fect­ed luciferase con­structs con­tain­ing either an
intact hor­mone-respon­sive pro­mot­er from the mam­malian PEPCK gene or two tandem
glu­co­cor­ti­coid response ele­ments (GRE). West­ern blot­ting and con­fo­cal microscopy
of a green flu­o­res­cent pro­tein-tagged-GR fusion pro­tein demon­strat­ed that
arsen­ite pre­treat­ment did not block the nor­mal dex­am­etha­sone-induced nuclear
translo­ca­tion of GR. These data indi­cate that non­tox­ic dos­es of arsen­ite can
inter­act direct­ly with GR com­plex­es and selec­tive­ly inhib­it GR-mediated
tran­scrip­tion, which is asso­ci­at­ed with altered nuclear func­tion rather than a
decrease in hor­mone-induced GR acti­va­tion or nuclear translocation.

MJTR: Arsen­ites, phar­ma­col­o­gy. Car­cino­gens, phar­ma­col­o­gy. Receptors,
Glu­co­cor­ti­coid, drug effects. Tran­scrip­tion Fac­tors, drug effects.

MNTR: Ani­mal. Arsenic Poi­son­ing, metab­o­lism. Blot­ting, West­ern. Carcinoma,
Hepa­to­cel­lu­lar, metab­o­lism. Pre­cip­itin Tests. Rats. Sup­port, U.S. Gov’t,
P.H.S.. Tumor Cells, Cultured.

RNUM: 0 (Arsen­ites); 0 (Car­cino­gens); 0 (Recep­tors, Glu­co­cor­ti­coid); 0
(Tran­scrip­tion Fac­tors); 15502–74‑6 (arsen­ite)

GEOT: Unit­ed States

IDEN: ISSN: 0091–6765. JOURNAL-CODE: EI0; 0330411. ENTRY-DATE: 20010502.
NIH-GRANT-NUMBER: CA23108/CA/NCI. ES07373/ES/NIEHS. SPECIAL-LIST: IM.
JOURNAL-SUBSET: IM.

ACCE: 21231571

PMID: 11333185