Contribution of L-3,4-dihydroxyphenylalanine metabolism to the inhibition of gluconeogenesis in rabbit kidney-cortex tubules.
The circulating L-3,4-dihydroxyphenylalanine, the drug of choice in the therapy of Parkinson's disease (PD), is efficiently extracted by kidney and converted to dopamine, known to control several renal functions. As: (i) in addition to liver, kidney is an important source of glucose in mammals and (ii) the action of this drug on renal gluconeogenesis has not yet been studied, the aim of the present investigation was to estimate the influence of L-3,4-dihydroxyphenylalanine metabolism on glucose formation in isolated kidney-cortex tubules incubated with various gluconeogenic substrates. The data indicate that a rapid intracellular degradation of L-3,4-dihydroxyphenylalanine and tyramine (at 100 and 200 microM concentrations) is accompanied by 25-40% decrease in glucose production from pyruvate, alanine + glycerol + octanoate and dihydroxyacetone due to augmented generation of hydrogen peroxide via monoamine oxidase B, resulting in a decline of glutathione redox state by 40%. Moreover, following inhibition of monoamine oxidase B by deprenyl or substitution of pyruvate by aspartate + glycerol + octanoate both L-3,4-dihydroxyphenylalanine and tyramine affect neither the rate of gluconeogenesis nor glutathione redox state. In view of: (i) L-3,4-dihydroxyphenylalanine- and tyramine-induced changes in intracellular levels of gluconeogenic intermediates, and (ii) a significant decline of phosphoenolpyruvate carboxykinase activity by 500 microM oxidized glutathione, it is likely that L-3,4-dihydroxyphenylalanine- and tyramine-evoked disturbances in the glutathione redox state might diminish flux through phosphoenolpyruvate carboxykinase and in consequence decrease glucose formation in renal tubules, suggesting a new potential side-action of L-3,4-dihydroxyphenylalanine treatment.
Drozak
Jakub
J
Department of Metabolic Regulation, Institute of Biochemistry, Warsaw University, ul. Miecznikowa 1, 02-096 Warszawa, Poland.
Doroszewska
Renata
R
Chodnicka
Katarzyna
K
Winiarska
Katarzyna
K
Bryla
Jadwiga
J
D000409:Alanine / Q000378:metabolism; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002210:Caprylates / Q000378:metabolism; D003864:Depression, Chemical; D004098:Dihydroxyacetone / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000494:pharmacology; D005990:Glycerol / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism*; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D011817:Rabbits; D012642:Selegiline / Q000494:pharmacology; D014439:Tyramine / Q000378:metabolism
D002210:Caprylates; D012642:Selegiline; D001224:Aspartic Acid; D007980:Levodopa; D019289:Pyruvic Acid; D006861:Hydrogen Peroxide; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005978:Glutathione; D004098:Dihydroxyacetone; C031492:octanoic acid; D000409:Alanine; D005990:Glycerol; D019803:Glutathione Disulfide; D004298:Dopamine; D014439:Tyramine