The effects of inhibiting choline dehydrogenase on choline metabolism in mice.
3,3-Dimethylbutanol (Dimbunol), a competitive inhibitor of choline dehydrogenase (CDH), and ethylcholine mustard aziridinium (ECMA), an effective irreversible inhibitor of both CDH and choline transport, were investigated for their effects upon the uptake and metabolism of [3H]choline in mice. Thirty minutes after Dimbunol administration (i.p. 0.5 mmoles/kg) a reduction in the rate of choline oxidation was accompanied by an inhibition of choline phosphorylation in the kidney. Choline had accumulated to 5-fold the control level. After ECMA (i.v. 4 mumoles/kg), kidney choline was elevated 18-fold and both oxidation and phosphorylation rates were severely inhibited. In the liver Dimbunol inhibited oxidation and phosphorylation of choline and generated a 2-fold rise in tissue choline. Ethylcholine mustard aziridinium inhibited both oxidation and phosphorylation in the liver to the same extent as in the kidney but produced only a 3-fold elevation of choline. Dimbunol failed to elevate serum choline 30 min after administration and brain choline and acetylcholine levels were also unchanged. Serum choline was doubled by ECMA. These studies suggest that both transport across the renal tubules and oxidation may be important in choline regulation, that high levels of choline may accumulate in the liver and kidney which are not available for acetylcholine synthesis but that longer term studies on the effects of Dimbunol might reveal useful ways of facilitating sustained elevation of serum choline in precursor therapy.
D000429:Alcohol Oxidoreductases / Q000037:antagonists & inhibitors*; D000818:Animals; D001388:Aziridines / Q000494:pharmacology*; D001389:Azirines / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002794:Choline / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D050545:Choline Dehydrogenase; D005260:Female; D000441:Hexanols / Q000494:pharmacology*; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects
D001388:Aziridines; D001389:Azirines; D000441:Hexanols; C007469:3,3-dimethylbutan-1-ol; C044894:ethylcholine aziridinium; D000429:Alcohol Oxidoreductases; D050545:Choline Dehydrogenase; D002794:Choline