Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:1.8.1.4 (
diaphorase
)
2,754
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We have demonstrated for the first time that mitoplasts (i.e. mitochondria without outer membrane) were able to convert stilbene estrogen (diethylstilbestrol,
DES
) to reactive metabolites, which covalently bind to mitochondrial (mt)DNA. Depending on the cofactor used, mitochondrial enzymes catalyzed the oxidation and/or reduction of
DES
.
DES
was oxidized to
DES
quinone by peroxide-supported mitochondrial enzyme. A Lineweaver-Burk plot of rate of formation of
DES
quinone at various substrate concentrations yielded a Km of 33 microM and Vmax of 39 nmol/mg protein/min. The oxidation of
DES
to
DES
quinone by mitochondria was drastically decreased by known inhibitors of cytochrome P450.
DES
quinone was reduced to
DES
by mitoplasts in the presence of NADH. The Km and Vmax for the
DES
quinone reduction in the absence of mitoplasts and NADH were 3.2 microM and 5.6 nmol respectively. The reduction of
DES
quinone to
DES
by mitoplasts was significantly inhibited by inhibitors of cytochrome b5 reductase and
diaphorase
.
DES
quinone was also reduced to
DES
by pure
diaphorase
, a mitochondrial reducing enzyme, in the presence of NADH. The Km and Vmax for the
DES
quinone reduction by
diaphorase
were 9.0 microM and 4.3 nmol respectively. Under reaction conditions similar to oxidation of
DES
to
DES
quinone by mitoplasts, it was observed that mitochondrial metabolic products of
DES
were able to covalently bind to mtDNA. These data provide direct evidence of mitochondrial enzyme-catalyzed oxidation and reduction reactions of
DES
. In the cell, activation of
DES
in the mitochondria (the organelle in which mtDNA synthesis, mtDNA repair and transcription systems are localized) is of utmost importance, because an analogous in vivo mitochondrial metabolism of
DES
through covalent modifications in mitochondrial genome may produce instability in the mitochondrial genome of the cells. These modifications may in turn play a role in the development of
DES
-induced hepatocarcinogenicity.
...
PMID:Mitochondrial enzyme-catalyzed oxidation and reduction reactions of stilbene estrogen. 772 71
