CHARACTERIZATION OF THE IN-VIVO INHIBITION OF RAT HEPATIC-MICROSOMAL ALDEHYDE DEHYDROGENASE-ACTIVITY BY METYRAPONE

Citation
R. Martini et M. Murray, CHARACTERIZATION OF THE IN-VIVO INHIBITION OF RAT HEPATIC-MICROSOMAL ALDEHYDE DEHYDROGENASE-ACTIVITY BY METYRAPONE, Biochemical pharmacology, 51(9), 1996, pp. 1187-1193
Citations number
30
Categorie Soggetti
Pharmacology & Pharmacy",Biology
Journal title
ISSN journal
00062952
Volume
51
Issue
9
Year of publication
1996
Pages
1187 - 1193
Database
ISI
SICI code
0006-2952(1996)51:9<1187:COTIIO>2.0.ZU;2-F
Abstract
Microsomal aldehyde dehydrogenase (mALDH; EC 1.2.1.3) has been propose d to catalyze the oxidation of various aldehydic products of lipid per oxidation, 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 xenobi otics 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 dehydrog enation was also dose-dependent with 70, 43, and 12% of the control ac tivity remaining following pretreatment with 25, 100, and 250 mg/kg me tyrapone, respectively. This decrease in microsomal decanal dehydrogen ase activity occurred without a change in mALDH immunoreactive protein , and metyrapone did not inhibit the activity in vitro. The kinetic an alysis revealed similar decreases in the maximal reaction velocities ( V-max) 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 ( K-m) were unchanged. These data are consistent with the in vivo inacti vation of a portion of the mALDH enzyme. A possible consequence of the in vivo inhibition of this enzyme by metyrapone could be the accumula tion of toxic aldehydes in the vicinity of the microsomal membrane fol lowing lipid peroxidation.