Differential effects of selegiline on glucose synthesis in rabbit kidney-cortex tubules and hepatocytes. In vitro and in vivo studies.
The action of selegiline, a selective and irreversible inhibitor of monoamine oxidase B, commonly applied in the therapy of Parkinson's disease, on glucose formation was investigated in isolated rabbit hepatocytes and kidney-cortex tubules, maintaining the whole body glucose homeostasis via gluconeogenic pathway activity. An intensive hepatic metabolism of selegiline resulted in formation of selegiline-N-oxide, desmethylselegiline, methamphetamine and amphetamine, whereas during slow degradation of the drug in freshly isolated renal tubules selegiline-N-oxide was mainly produced. At 100 microM concentration selegiline markedly diminished glucose synthesis in isolated renal tubules incubated with dihydroxyacetone or alanine+glycerol+octanoate (by about 60 and 30%, respectively), while at 5 microM concentration a similar degree of inhibition was achieved in renal tubules grown in primary culture under the same conditions (about 40 and 60%, respectively). Moreover, desmethylselegiline and selegiline-N-oxide considerably diminished glucose production in renal tubules whereas selegiline and its metabolites did not affect gluconeogenesis in hepatocytes. Contrary to control animals, following selegiline administration to alloxan-diabetic rabbits for 8 days (10 mg kg(-1) body wt. daily) the blood glucose and serum creatinine levels were significantly diminished, suggesting a decrease in renal gluconeogenesis and improvement of kidney functions. Since in renal tubules selegiline induced a decline in the intracellular levels of gluconeogenic intermediates and ATP content accompanied by a decrease in oxygen consumption in both kidney-cortex and hepatic mitochondria it seems possible that its inhibitory action on renal gluconeogenesis might result from an impairment of mitochondrial function, while an intensive selegiline metabolism in hepatocytes causes decrease of its concentration and in consequence no inhibition of gluconeogenesis. In view of these observations it is likely that an increased risk of selegiline-induced hypoglycemia might be expected particularly in patients exhibiting an impairment of liver function and following transdermal administration of this drug, i.e. under conditions of increased serum selegiline concentrations.
Drozak
Jakub
J
Department of Metabolic Regulation, Faculty of Biology, University of Warsaw, ul. I. Miecznikowa 1, 02-096 Warszawa, Poland.
Kozlowski
Marcin
M
Doroszewska
Renata
R
Pera
Lukasz
L
Derlacz
Rafal
R
Jarzyna
Robert
R
Bryla
Jadwiga
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D005947:Glucose / Q000096:biosynthesis*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D012642:Selegiline / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism
D013481:Superoxides; D012642:Selegiline; D000255:Adenosine Triphosphate; D005947:Glucose; D010100:Oxygen