Metabolism of cyanamide to cyanide and an inhibitor of aldehyde dehydrogenase (ALDH) by rat liver microsomes.
Rat liver microsomes, as well as purified catalase, convert the alcohol deterrent agent, cyanamide, to an active inhibitor of AlDH. Whether this enzymatic activation of cyanamide is mediated primarily by catalase present in the microsomes or involves the cytochrome P-450 enzymes is not known. We now report that cyanide is also a product of the microsomal oxidation of cyanamide. Formation of cyanide from cyanamide and rat liver microsomes was time dependent, reaching maximal levels within 5-10 min. Induction of the cytochrome P-450 enzymes by phenobarbital (PB) pretreatment doubled the yield of cyanide, while SKF-525A blocked this PB-induced increase. Administration of 3-aminotriazole (3-AT) to PB-treated rats inhibited the catalatic activity of their microsomes by 98% and substantially reduced cyanide formation. These results suggest that while catalase is responsible in major part for the oxidation of cyanamide to cyanide by uninduced microsomes, the participation of the hepatic cytochrome P-450 enzymes cannot be ruled out in PB-induced microsomes. We propose a metabolic scheme wherein N-hydroxycyanamide is the intermediate product of cyanamide oxidation, which then decomposes to yield the observed product, cyanide. By deduction, the second product of this decomposition is postulated to be nitroxyl (HNO), which may be the active AlDH inhibitor.
Medical Research Laboratories, VA Medical Center, Minneapolis, MN.
F N
FN
Shirota
E G
EG
DeMaster
C H
CH
Kwon
H T
HT
Nagasawa
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000640:Amitrole / Q000494:pharmacology; D000818:Animals; D003484:Cyanamide / Q000493:pharmacokinetics*; D003486:Cyanides / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D003486:Cyanides; D003484:Cyanamide; D000444:Aldehyde Dehydrogenase; D010634:Phenobarbital; D000640:Amitrole