Alloxan and ninhydrin inhibition of hexokinase from pancreatic islets and tumoural insulin-secreting cells.
Alloxan inhibited hexokinase activity in cytoplasmic fractions of transplantable radiation-induced rat islet cell tumours, ob/ob mouse pancreatic islets, rat liver and rat kidney. Half maximal inhibitory concentrations of alloxan were greater than those previously found for half maximal inhibition of pancreatic islet or liver glucokinase. D-glucose, preferentially the alpha-anomer, and D-mannose protected hexokinase activity against alloxan inhibition. 1,4-Dithiothreitol completely protected against and partially reversed the alloxan inhibition of hexokinase. The ability of various dithiols to reverse the inhibition of hexokinase by alloxan was dependent on the spacing between the SH (thiol) groups. Only dithiols with intermediate spacing between the SH groups were effective. Dithiols with two vicinal SH groups such as 1,2-dimercaptoethane and 2,3-dimercaptopropanol (BAL) and dithiols with more widely spaced SH groups such as 1,5-dimercaptopentane were ineffective. Thus a reaction of alloxan with two SH groups in the sugar binding site of the hexokinase with the formation of a disulfide bond may be involved in the reversible inhibition of the enzyme. Ninhydrin also inhibited hexokinase from all four tissues studied. The half maximal inhibitory concentrations of ninhydrin were lower than those of alloxan. Inhibition of hexokinase may be an important factor in the general cytotoxic action of ninhydrin. However, inhibition of pancreatic islet hexokinase is unlikely to be the initial event in the pancreatic B-cell toxic action of alloxan, even if inhibition of hexokinase by high concentrations of alloxan may contribute to the B-cell toxic action.(ABSTRACT TRUNCATED AT 250 WORDS)
Lenzen
S
S
Institute of Pharmacology and Toxicology, University of Göttingen, Federal Republic of Germany.
Freytag
S
S
Panten
U
U
Flatt
P R
PR
Bailey
C J
CJ
D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D004229:Dithiothreitol / Q000494:pharmacology; D006593:Hexokinase / Q000037:antagonists & inhibitors*; D007192:Indenes / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008815:Mice, Inbred Strains; D009555:Ninhydrin / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D007192:Indenes; D007328:Insulin; D000496:Alloxan; D006593:Hexokinase; D009555:Ninhydrin; D004229:Dithiothreitol