Paraquat inhibits progesterone synthesis in human placental mitochondria
Graphical abstract
Introduction
Paraquat (PQ) is a highly toxic herbicide and the intoxication of humans by this compound often leads to death or serious multi-organ failure. Most cases of the PQ poisoning are related to farming and have accidental nature, although suicide cases have also been noted. If a pregnant woman is a victim of such poisoning, apart from the typical effects of poisoning, the metabolism of fetus and placenta can be affected as well [1], [2]. That should be expected because PQ concentration in fetal blood is 4–6 times higher than in mother blood [1], [2].
Human placenta produces large quantities of progesterone – necessary to maintain pregnancy [3]. This production is localized in the inner mitochondrial membrane and consist of two consecutive steps [4], [5] first of which is the conversion of cholesterol to pregnenolone that is catalyzed by cholesterol desmolase (cytochrome P450scc, CYP11A) whereas the second is the conversion of pregnenolone to progesterone catalyzed by 3β-hydroxysteroid dehydrogenase/Δ5,4-isomerase (3β-HSD).
It has been previously shown that iron- and NADPH-dependent lipid peroxidation inhibits progesterone synthesis in human placental mitochondria (HPMit) which are very susceptible to lipid peroxidation [6], [7], [8], [9]. It is also well documented that PQ can be easily reduced by a one-electron process forming in consequence superoxide radical [10], [11]that promotes lipid peroxidation and the injury of cells [12], [13]. These premises have persuaded us to study the hypothesis according to which PQ can inhibit human placental steroidogenesis in mitochondria and this possibility is the main aim of the study presented here.
Section snippets
Chemicals
Butylated hydroxytoluene (BHT), FeCl2, glucose-6-phosphate (G-6-P), glucose-6-phosphate dehydrogenase, NADPH, paraquat (PQ), superoxide dismutase (SOD), thiobarbituric acid (TBA) were purchased from Sigma-Aldrich. [4-14C]cholesterol and [4-14C]pregnenolone were obtained from Radiochemical Centre (Amersham, England). [3H]progesterone and [3H]pregnenolone were obtained from PerkinElmer (Boston, USA). Silica Gel G and Rhodamine 6G were purchased from Merck. All other materials were of the highest
The effect of PQ on lipid peroxidation and progesterone synthesis in human placental mitochondria
Owing to its chemical properties, paraquat (PQ) should be considered independently as an enhancer of lipid peroxidation (iron-dependent or iron-independent) and also as a chemical compound acting directly on progesterone synthesis. Hence, we measured the action of paraquat on progesterone synthesis and lipid peroxidation both in the presence and absence of iron. As presented in Table 1 the addition of iron to the incubation mixture caused huge increase in TBARS (tiobarbituric acid – reactive s
Discussion
Our findings have shown for the first time the inhibitory action of PQ on progesterone synthesis in human placental mitochondria. Taking into consideration the oxidoreductive nature of PQ, we supposed that it would inhibit the synthesis of the progesterone thanks to free radicals. Our previous results have shown that lipid radicals formed during iron-dependent lipid peroxidation caused degradation of steroidogenic cytochromes P450 and in consequence – the inhibition of pregnenolone synthesis in
Conclusions
Our findings have shown for the first time the inhibitory action of PQ on progesterone synthesis in human placental mitochondria. On the basis of our results we conclude that the most important reason of this phenomenon is the escape of electrons from cytochrome P450scc to PQ leading the cytochrome P450scc oxidation and, in consequence the inhibition of the synthesis of pregnenolone – direct precursor of progesterone. The action of PQ described here should be considered as potentially harmful
Acknowledgments
This work was supported by a grant ST-40 from Medical University of Gdańsk, within the grant from Polish Ministry of Science and Higher Education.
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