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
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.