This study focuses on the alterations suffered by the serotoninergic and kinurenergic routes of
tryptophan (TRP) metabolism in liver, and their relation with gluconeogenic
phosphoenolpyruvate-carboxykinase (PEPCK) blockage in experimental
acute porphyria. This
porphyria was induced in rats by a combined treatment of 2-allyl-2-isopropylacetamide (100, 250, 500 mg/kg bw) and 3,5-dietoxicarbonil 1,4-dihydrocollidine (constant 50 mg/kg bw dose). Results showed a marked dose-dependent increase of all TRP pyrrolase (TRPp) forms, active (holo, total) and inactive (apo), and a decrease in the degree of
enzyme saturation by
heme. Increases for holo, total, and apo-TRPp were 90, 150, and 230%, respectively, at the highest dose assayed (H). The treatment also impaired the serotoninergic route of TRP metabolism in liver, causing a decrease in
serotonin level (H, 38%), and a concomitant enhancement in TRP content (H, 23%). The porphyrinogenic treatment promoted a blockage in PEPCK activity (H, 30%). This occurred in correlation to the development of
porphyria, to TRPp alterations and to the production of hepatic microsomal
thiobarbituric acid reactive substances.
Porphyria was estimated through increases in 5-aminolevulinic
acid-synthase (ALA-S) activity, ALA and
porphobilinogen contents, and a decrease in
ferrochelatase activity. Thus, the TRP
kynurenine route was augmented whereas the serotoninergic route was reduced. PEPCK blockage could be partly attributed to
quinolinate generated from TRP by the increase of TRPp activity, which would be due to the effect of porphyrinogenic drugs on TRP. The contribution of ROS to PEPCK blockage is analyzed. Likewise, the implication of these results in the control of
porphyrias by
glucose is discussed.