Acute effects of the aldehyde dehydrogenase inhibitors, disulfiram, pargyline and cyanamide, on circulating ketone body levels in the rat.
Acetonemia is generally associated with the ketogenic states of fasting and diabetes. Disulfiram (DS), an inhibitor of aldehyde dehydrogenase (AlDH) that is used as an alcohol deterrent drug, is also known to elevate blood acetone in humans, but in the absence of a commensurate increase in its metabolic precursor, acetoacetate. We reexamined the effects of DS and other AlDH inhibitors on circulating ketone body levels in male rats of Sprague-Dawley descent and again demonstrated a 6- and 16-fold increase in blood acetone along with normal levels of acetoacetate at 6 and 24 hr after DS. Pargyline, another inhibitor of AlDH, maintained normal blood acetone levels in the presence of reduced acetoacetate levels. A third inhibitor of AlDH, cyanamide, administered to fasted and nonfasted rats, elevated blood acetone levels 10-fold over controls, with, however, a commensurate 5- and 7-fold increase in blood acetoacetate levels. The threshold values for the cyanamide-induced elevation of blood acetone and acetoacetate were equivalent, i.e. approximately 0.25 mmol/kg body weight (i.p.). The elevation of acetoacetate and the inhibition of hepatic catalase activity by cyanamide are not mechanistically linked, since 3-amino-1,2,4-triazole, another inhibitor of catalase, elevated blood acetone but not acetoacetate levels. These findings suggest that DS-induced acetonemia is due to inhibition of acetone metabolism, whereas enhanced acetone formation through acetoacetate contributes significantly to cyanamide-induced acetonemia.
DeMaster
E G
EG
Medical Research Laboratories, VA Medical Center, Minneapolis, MN 55417.
Stevens
J M
JM
D020155:3-Hydroxybutyric Acid; D000090:Acetoacetates / Q000097:blood; D000096:Acetone / Q000097:blood; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D003484:Cyanamide / Q000494:pharmacology*; D003486:Cyanides / Q000494:pharmacology*; D004221:Disulfiram / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology; D006885:Hydroxybutyrates / Q000097:blood; D007657:Ketone Bodies / Q000097:blood*; D007700:Kinetics; D008297:Male; D010293:Pargyline / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D000090:Acetoacetates; D003486:Cyanides; D006885:Hydroxybutyrates; D007657:Ketone Bodies; D000096:Acetone; D000431:Ethanol; D003484:Cyanamide; C016635:acetoacetic acid; D010293:Pargyline; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram; D020155:3-Hydroxybutyric Acid