Hepatic alteration of tryptophan metabolism in an acute porphyria model Its relation with gluconeogenic blockage.
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.
Lelli
Sandra M
SM
Laboratorio de Disturbios Metabólicos por Xenobióticos, Salud Humana y Medio Ambiente (DIMXSA), Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
Mazzetti
Marta B
MB
San Martín de Viale
Leonor C
LC
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism; D000208:Acute Disease; D000502:Allylisopropylacetamide / Q000633:toxicity; D000818:Animals; D003997:Dicarbethoxydihydrocollidine / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D005943:Gluconeogenesis; D008099:Liver / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000037:antagonists & inhibitors*; D011164:Porphyrias / Q000139:chemically induced / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014364:Tryptophan / Q000378:metabolism*
D000502:Allylisopropylacetamide; D003997:Dicarbethoxydihydrocollidine; D014364:Tryptophan; D000624:5-Aminolevulinate Synthetase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)