This work deals with the study of how porphyrinogenic drugs modeling
acute porphyrias interfere with the status of
carbohydrate-regulating
hormones in relation to key
glucose enzymes and to
porphyria, considering that
glucose modulates the development of the disease. Female Wistar rats were treated with 2-allyl-2-isopropylacetamide (AIA) and
3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) using different doses of AIA (100, 250 and 500mg/kg
body weight) and a single dose of DDC (50mg DDC/kg
body weight). Rats were sacrificed 16h after AIA/DDC administration. In the group treated with the highest dose of AIA (group H), hepatic 5-aminolevulinic
acid synthase (ALA-S) increased more than 300%,
phosphoenolpyruvate carboxykinase (PEPCK) and
glycogen phosphorylase (GP) activities were 43% and 46% lower than the controls, respectively, plasmatic
insulin levels exceeded normal values by 617%, and plasmatic
glucocorticoids (GC) decreased 20%. GC results are related to a decrease in
corticosterone (CORT) adrenal production (33%) and a significant reduction in its metabolization by
UDP-glucuronosyltransferase (UGT) (62%).
Adrenocorticotropic hormone (
ACTH) stimulated adrenal production 3-fold and drugs did not alter this process. Thus,
porphyria-inducing drugs AIA and DDC dramatically altered the status of
hormones that regulate carbohydrate metabolism increasing
insulin levels and reducing GC production, metabolization and plasmatic levels. In this
acute porphyria model, gluconeogenic and glycogenolytic blockages caused by PEPCK and GP depressed activities, respectively, would be mainly a consequence of the negative regulatory action of
insulin on these
enzymes. GC could also contribute to PEPCK blockage both because they were depressed by the treatment and because they are positive effectors on PEPCK. These disturbances in
carbohydrates and their regulation, through ALA-S de-repression, would enhance the
porphyria state promoted by the drugs on
heme synthesis and destruction. This might be the mechanism underlying the "
glucose effect" observed in
hepatic porphyrias. The statistical correlation study performed showed association between all the variables studied and reinforce these conclusions.