INVESTIGADORES
BUZALEH Ana Maria
congresos y reuniones científicas
Título:
Effects of volatile anaesthetics on heme metabolism in a murine model of Acute Intermittent
Autor/es:
RUSPINI, SILVINA; ZUCCOLI, JOHANNA; LAVANDERA JIMENA; BATLLE, ALCIRA; BUZALEH, ANA MARIA
Lugar:
Lucerna
Reunión:
Congreso; INTERNATIONAL CONGRESS ON PORPHYRINS AND PORPHYRIAS; 2013
Resumen:
The anaesthetics Isoflurane and Sevoflurane reproduced the typical
biochemical signs of Acute Intermittent Porphyria (AIP) when they
were administered to CF1 mice. The aim was to evaluate the effects
of these xenobiotics on heme metabolism in a mouse model of AIP to further support our previous proposal for avoiding their use in porphyric
patients. A comparative study was performed with the porphyrinogenic
drugs allylisopropylacetamide (AIA) and ethanol.
Males and females knockout deficient mice for the enzyme Porphobilinogen
Deaminase (PBG-D) were used: PBGD -/- (activity 70 %
reduced) and PBGD + /- (activity 50 % diminished). The anaesthetics
were administered in one dose of 2 ml/kg (Isoflurane) or 1.5 ml/kg
(Sevoflurane); animals were sacrificed 20 minutes after injection. AIA
was given in one dose of 350 ml/kg, 16 hours prior to the sacrifice.
Ethanol was present in the drinking water (30 % ) during one week.
The activity and expression of 5-Aminolevulinic synthetase
(ALA-S) and the activity of PBG-D were measured in liver, brain,
kidney and blood. Isoflurane increased ALA-S activity in liver (40 % ,
p < 0.05) and kidney (46 % , p < 0.05) of PBGD -/- male mice; while in
PBGD + /- , the induction (160 % , p < 0.01) was only observed in liver.
Sevoflurane increased ALA-S activity in female groups: kidney
(100%, p < 0.05) and brain (163 % , p < 0.01) of PBGD -/- mice; liver (248 % ,
p < 0.01) and brain (550 % , p < 0.01) of PBGD + /- mice. Isoflurane reduced
25 % (p < 0.05) PBG-D activity in liver of PBGD + /- male mice; while in
PBGD -/- male mice the decrease was 40 % in liver (p < 0.05) and 18% in
brain (p < 0.05). Sevoflurane reduced PBG-D activity only in liver (55 % ,
p < 0.05) and kidney (80 % , p < 0.05) of female heterozygote group.
When PBGD -/- groups received AIA, hepatic ALA-S activity
was strikingly induced in males (7 folds, p < 0.01) and females (14
folds; p < 0.01) while PBG-D activity was unchanged. AIA triggered
in male PBGD -/- mice neurological signs similar to those observed
during human acute attacks; the symptoms were less pronounced in
females in spite that ALA-S activity was several times more induced.
In PBGD + /- mice, ALA-S induction caused by AIA was lower than in
PBGD -/- mice without clinical alterations. Ethanol caused biochemical
alterations depending on the group studied but without clinical
manifestations.
In conclusion, male mice were more affected by porphyrinogenic
drugs, a fact different to that observed in humans, where the
onset of AIP mainly occurs in females.