Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde.
Biotransformation of the biologically and pharmacologically important aldehydes, retinaldehyde and aldophosphamide, is mediated, in part, by NAD(P)-dependent aldehyde dehydrogenases catalyze the oxidation of the aldehydes to their respective acids, retinoic acid and carboxyphosphamide. Not known at the onset of this investigation was which of the several known human aldehyde dehydrogenases (ALDHs) catalyze these reactions. Thus, human liver aldehyde dehydrogenases were chromatographically resolved and the ability of each to catalyze the oxidation of retinaldehyde and aldophosphamide was assessed. Only one, namely ALDH-1, catalyzed the oxidation of retinaldehyde; the Km value was 0.3 microM. Three, namely ALDH-1, ALDH-2 and succinic semialdehyde dehydrogenase, catalyzed the oxidation of aldophosphamide; Km values were 52, 1193, and 560 microM, respectively. ALDH-4, ALDH-5 and betaine aldehyde dehydrogenase did not catalyze the oxidation of either aldophosphamide or retinaldehyde. ALDH-1 and succinic semialdehyde dehydrogenase accounted for 64 and 30%, respectively, of the total hepatic aldehyde dehydrogenase-catalyzed aldophosphamide (160 microM) oxidation. ALDH-1-catalyzed oxidation of aldophosphamide was noncompetitively inhibited by chloral hydrate; the Ki value was 13 microM. ALDH-2- and succinic semialdehyde dehydrogenase-catalyzed oxidation of aldophosphamide was relatively insensitive to inhibition by chloral hydrate. These observations strongly suggest an important in vivo role for ALDH-1 in the catalysis of retinaldehyde and aldophosphamide biotransformation. Succinic semialdehyde dehydrogenase-catalyzed biotransformation of aldophosphamide may also be of some in vivo importance.
Dockham
P A
PA
Department of Pharmacology, University of Minnesota Medical School, Minneapolis 55455.
Lee
M O
MO
Sladek
N E
NE
D000328:Adult; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000302:isolation & purification* / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001711:Biotransformation; D002675:Child, Preschool; D002697:Chloral Hydrate / Q000494:pharmacology; D005260:Female; D006801:Humans; D007525:Isoelectric Focusing; D007526:Isoelectric Point; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000302:isolation & purification* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D010752:Phosphoramide Mustards / Q000378:metabolism*; D012172:Retinaldehyde / Q000378:metabolism*; D050644:Succinate-Semialdehyde Dehydrogenase; D014212:Tretinoin / Q000378:metabolism
D007527:Isoenzymes; D010752:Phosphoramide Mustards; D002697:Chloral Hydrate; D014212:Tretinoin; C006446:aldophosphamide; C000028:carboxyphosphamide; D000445:Aldehyde Oxidoreductases; C493643:ALDH5A1 protein, human; D050644:Succinate-Semialdehyde Dehydrogenase; D000444:Aldehyde Dehydrogenase; D012172:Retinaldehyde