Paraquat inhibits progesterone synthesis in human placental mitochondria.
Human placenta mitochondria produces huge amounts of progesterone necessary for maintaining the pregnancy. Lipid peroxidation in human placental mitochondria inhibits progesterone synthesis and that inhibition can be reversed by superoxide dismutase and other antioxidants. Paraquat (PQ) a highly toxic herbicide generates superoxide radical inside cells and induces lipid peroxidation. Hence, it is supposed to stimulate lipid peroxidation in human placental mitochondria and in consequence to inhibit a placental mitochondrial steroidogenesis.



Placentas were obtained from normal pregnancies. All experiments were done using isolated human placental mitochondria. Mitochondrial lipid peroxidation was determined as tiobarbituric acid reactive substances (TBARS). A conversion of cholesterol to pregnenolone or pregnenolone to progesterone was measured using radiolabeled steroids and thin layer chromatography.



PQ enhanced the iron-dependent lipid peroxidation as also PQ heightened the inhibitory action of this process on progesterone synthesis in isolated human placental mitochondria. Paradoxically, a superoxide dismutase (SOD) reversed the inhibition of progesterone synthesis only minimally although it strongly inhibited PQ stimulated iron-dependent lipid peroxidation. When iron was absent, PQ stimulated only negligible lipid peroxidation but strongly inhibited progesterone synthesis. SOD had no effect on inhibition of progesterone synthesis by PQ. PQ strongly inhibited of the conversion of cholesterol to pregnenolone but had not got any influence on the enzymatic activity of mitochondrial 3β-hydroxysteroid dehydrogenase. PQ strongly decreased the efficiency of NADPH-dependent cytochrome P450 reduction as well as it promoted the rapid oxidation of the pre-reduced mitochondrial cytochrome P450. However PQ has not inhibited combined activity of adrenodoxin reductase and adrenodoxin.



We conclude that the most important reason of the inhibition of progesterone synthesis by PQ is the escape of electrons from cytochrome P450scc to that compound what leads to cytochrome oxidation and, in consequence the inhibition of the reaction catalyzed by it. The action of PQ described here should be considered as potentially harmful for pregnancy and fetal development.
Department of Pharmaceutical Biochemistry, Medical University of Gdańsk, Gdańsk, Poland. Electronic address: rysmil@gumed.edu.pl.
Ryszard
R
Milczarek
Department of Pharmaceutical Biochemistry, Medical University of Gdańsk, Gdańsk, Poland.
Ewa
E
Sokołowska
Department of Biochemistry and Clinical Physiology, Medical University of Gdańsk, Gdańsk, Poland.
Iwona
I
Rybakowska
Department of Biochemistry and Clinical Physiology, Medical University of Gdańsk, Gdańsk, Poland.
Krystian
K
Kaletha
Department of Pharmaceutical Biochemistry, Medical University of Gdańsk, Gdańsk, Poland.
Jerzy
J
Klimek
D002784:Cholesterol / Q000378:metabolism; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism; D005260:Female; D006540:Herbicides / Q000494:pharmacology*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010269:Paraquat / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D011374:Progesterone / Q000096:biosynthesis*; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D006540:Herbicides; D017392:Thiobarbituric Acid Reactive Substances; D011374:Progesterone; D002784:Cholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme; D010269:Paraquat
CYP11A1; Human placenta; Lipid peroxidation; Mitochondria; Paraquat; Progesterone biosynthesis