Effects of volatile anaesthetics on heme metabolism in a murine model of Acute Intermittent Porphyria. A comparative study with other porphyrinogenic drugs

RUSPINI, SILVINA; ZUCCOLI, JOHANNA; LAVANDERA, JIMENA; BATLLE, ALCIRA; BUZALEH, ANA MARÍA

Lucerna

Congreso; INTERNATIONAL CONGRESS ON PORPHYRINS AND PORPHYRIAS; 2013

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.