Melatonin modulates drug-induced acute porphyria

• Melatonin partially eliminates the AIA/DDC-induced decrease in the activity of the gluconeogenic enzymes PEPCK and G6Pase.
• Melatonin favors a glucose-mediated down-regulating effect on AIA/DDC-induced ALA-S.
• Melatonin reduces AIA/DDC-increases in lipid peroxidation.
• Melatonin partially reverts the AIA/DDC-induced increase in ALA and PBG levels.
• The results obtained suggest the hypothetical use of Mel as co-treatment for acute porphyria.

This work investigated the modulation by melatonin (Mel) of the effects of the porphyrinogenic drugs 2-allyl-2-isopropylacetamide (AIA) and 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-collidine (DDC) on oxidative environment, glucose biosynthesis and heme pathway parameters. Administration of Mel before rat intoxication with AIA/DDC showed a clear beneficial effect in all cases. Mel induced decreases of 42% and 35% in the excretion of the hemeprecursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), respectively, and a 33% decrease in the induction of the heme regulatory enzyme 5-aminolevulinic acid-synthase (ALA-S). The activity of the glucose metabolism enzyme phosphoenolpyruvate carboxykinase (PEPCK), which had been diminished by the porphyrinogenic treatment, was restored by 45% when animals were pre-treated with Mel. Mel abolished the modest decrease in glucose 6-phospatase (G6Pase) activity caused by AIA/DDC treatment. The oxidative status of lipids was attenuated by Mel treatment in homogenates by 47%, whereas no statistically significant AIA/DDC-induced increase in thiobarbituric acid reactive substances (TBARS) was observed in microsomes after Mel pre-treatment. We hypothesize that Mel may be scavenging reactive species of oxygen (ROS) that could be damaging lipids, PEPCK, G6Pase and ferrochelatase (FQ). Additionally, Mel administration resulted in the repression of the key enzyme ALA-S, and this could be due to an increase in glucose levels, which is known to inhibit ALA-S induction. The consequent decrease in levels of the heme precursors ALA and PBG had a beneficial effect on the drug-induced porphyria. The results obtained open the possibility of further research on the use of melatonin as a co-treatment option in acute porphyria.