INHIBITORY EFFECT OF FREE-RADICALS DERIVED FROM ORGANIC HYDROPEROXIDEON PROGESTERONE SYNTHESIS IN HUMAN TERM PLACENTAL MITOCHONDRIA

Different natural and synthetic organic hydroperoxides have been found to stimulate TEARS formation in human term placental mitochondria. Th e levels of TEARS were lower than arising from NADPH-dependent lipid p eroxidation. BHT, Mn2+ and DMPO counteracted TEARS formation in the pr esence of cumene hydroperoxide implicating involvement of free radical s in this process; On the other hand superoxide dismutase, catalase an d EDTA while being inhibitory in NADPH-dependent Lipid peroxidation di d not inhibit cumene hydroperoxide-dependent TEARS formation. Amphenon e B and SKF-525A, inhibitors of cytochrome P-450, strongly inhibit bot h NADPH-and cumene hydroperoxide-dependent lipid peroxidation. These d ata provide evidence that cytochrome P-450(SCC) is involved in both th ese processes. However NADPH-dependent lipid peroxidation and the cume ne hydroperoxide have been found to inactivate placental mitochondrial cytochrome P-450(SCC). The presence of cumene hydroperoxide resulted in a more rapid inactivation of cytochrome P-450(SCC) and consequently inhibited NADPH-dependent lipid peroxidation. It has been observed fo r the first time that progesterone biosynthesis can be inhibited by cu mene hydroperoxide. Protective effect of Mn2+ and DMPO on progesterone biosynthesis indicates the importance of free radicals as transient p roducts of cytochrome P-450(SCC)-dependent cumene hydroperoxide metabo lism. In contrast to progesterone formation from cholesterol, the conv ersion of pregnenolone to progesterone was not affected by cumene hydr operoxide. This suggests that inhibition of progesterone synthesis fro m cholesterol by hydroperoxide may be ascribed to its effect on the de smolase activity of cytochrome P-450(SCC) in placental mitochondria. O n the basis of the results obtained, we propose that the inhibition of progesterone biosynthesis by naturally occurring hydroperoxides may c ontribute to the development of preeclampsia. (C) 1998 Elsevier Scienc e Inc.