NADPH- and iron-dependent lipid peroxidation inhibit aromatase activity in human placental microsomes.
During pregnancy placenta is the most significant source of lipid hydroperoxides and other reactive oxygen species (ROS). The increased production of lipid peroxides and other ROS is often linked to pre-eclampsia. It is already proved that placental endoplasmic reticulum may be an important place of lipid peroxides and superoxide radical production. In the present study we revealed that NADPH- and iron-dependent lipid peroxidation in human placental microsomes (HPM) inhibit placental aromatase--a key enzyme of estrogen biosynthesis in human placenta. We showed that significant inhibition of this enzyme is caused by small lipid peroxidation (TBARS (thiobarbituric acid-reactive substances)<4nmol/mg microsomal protein (m.p.)). More intensive lipid peroxidation (TBARS>9nmol/mg microsomal protein) diminishes aromatase activity to value being less than 5% of initial value. NADPH- and iron-dependent lipid peroxidation also causes disappearance of cytochrome P450 parallel to observed aromatase activity inhibition. EDTA, alpha-tocopherol, MgCl(2) and superoxide dismutase (SOD) prevent aromatase activity inhibition and cytochrome P450(AROM) degradation. Mannitol and catalase have not effect on TBARS synthesis, aromatase activity and cytochrome P450 degradation. In view of the above we postulate that the inhibition of aromatase activity observed is mainly a consequence of cytochrome P450(AROM) degradation induced by lipid radicals. The role of hydroxyl radical in cytochrome P450 degradation is negligible in our experimental conditions. The results presented here also suggest that the inhibition of aromatase activity can also take place in placenta at in vivo conditions.
Milczarek
Ryszard
R
Department of Pharmaceutical Biochemistry, Medical University of Gdańsk, ul. Debinki 1, 80-211 Gdańsk, Poland. rysmil@amg.gda.pl
Sokołowska
Ewa
E
Hallmann
Anna
A
Kaletha
Krystian
K
Klimek
Jerzy
J
D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D007501:Iron / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009249:NADP / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D011247:Pregnancy; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013997:Time Factors
D047072:Aromatase Inhibitors; D017392:Thiobarbituric Acid Reactive Substances; D009249:NADP; D007501:Iron; D001141:Aromatase