A classical
acute porphyria model in rats consists of combined treatment with 2-allyl-2-isopropylacetamide (AIA) and
3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). The present work describes the effects of this treatment on the
pentose phosphate (PP) pathway, glutahione metabolism and redox state and how they contribute to alter the
glucose pool of hepatocytes and modulate
porphyria, in Wistar rat livers. Our approach is based on the fact that
glucose is a repressor of 5-aminolevulinic synthase (ALA-S), the rate-limiting
enzyme of the
heme pathway, and treatment with AIA/DCC causes oxidative stress. Different doses of the xenobiotcs were used. The results show that AIA (500 mg/kg
body weight [BW])/DDC (50 mg/kg [BW]) treatment increased
glutathione peroxidase (GPx) activity by 46%, decreased both
glutathione reductase (GR) and
glutathione S-transferase (GST) activity by 69% and 52%, respectively, and reduced by 51%
reduced glutathione (GSH) and increased by 100%
glutathione disulfide (
GSSG) concentrations, therefore lowering by four-fold the GSH/
GSSG ratio. The activity of
glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting
enzyme of PP-pathway, was increased by 129% as well as that of
6-phosphogluconate dehydrogenase.
NADPH and the
NADPH/
NADP(+) ratio were increased by 14% and 28%, respectively. These effects could be attributed to the generation of
reactive oxygen species (ROS) elicited by the porphyrinogenic treatment, shown by enhanced DNA damage and ROS production. G6PD stimulation would decrease hepatic
glucose concentrations and consequently exacerbate the
porphyria. A decrease in
glucose could stimulate ALA-S and this would add to the effect of
drug-induced
heme depletion. Since the key role of GST is to inactivate toxic compounds, the drastic fall in its activity together with the accumulation of ALA would account for the symptoms of this hepatic disease model. The present findings show the high metabolic interplay between pathways and constitute a relevant contribution to achieve a better treatment of acute human
porphyria.