Characterization of the in vivo inhibition of rat hepatic microsomal aldehyde dehydrogenase activity by metyrapone.
Microsomal aldehyde dehydrogenase (mALDH; EC 1.2.1.3) has been proposed to catalyze the oxidation of various aldehydic products of lipid peroxidation, but the regulation of the enzyme has not been characterized. Metyrapone administration (100 mg/kg, i.p.) produced a rapid decline in the rates of mALDH-catalyzed decanal dehydrogenation; other xenobiotics were generally without effect. Thus, a 22% decrease in activity was detected 2 hr following metyrapone administration, and 52% of the activity remained at 6 hr. The decrease in microsomal decanal dehydrogenation was also dose-dependent with 70, 43, and 12% of the control activity remaining following pretreatment with 25, 100, and 250 mg/kg metyrapone, respectively. This disease in microsomal decanal dehydrogenase activity occurred without a change in mALDH immunoreactive protein, and metyrapone did not inhibit the activity in vitro. The kinetic analysis revealed similar decreases in the maximal reaction velocities (Vmax) for both decanal and NAD in the metyrapone-treated group (200 +/- 10 and 190 +/- 20 nmol NADH produced/min/mg protein, respectively) compared with the untreated group (330 +/- 10 and 350 +/- 20 nmol NADH produced/min/mg protein, respectively), but the Michaelis constants (Km) were unchanged. These data are consistent with the in vivo inactivation of a portion of the mALDH enzyme. A possible consequence of the in vivo inhibition of this enzyme by metyrapone could be the accumulation of toxic aldehydes in the vicinity of the microsomal membrane following lipid peroxidation.
Martini
R
R
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Murray
M
M
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006865:Hydrogenation; D008297:Male; D008797:Metyrapone / Q000493:pharmacokinetics / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D000447:Aldehydes; D004791:Enzyme Inhibitors; D011725:Pyridines; C021170:decanaldehyde; D000444:Aldehyde Dehydrogenase; D008797:Metyrapone