The reoxidation of cytochrome P-450 by paraquat inhibits aldosterone biosynthesis from 18-hydroxycorticosterone.
Paraquat is an artificial electron carrier that captures electrons from reduced cytochrome P-450 instead of the natural acceptors, thus decreasing the concentration of reduced mitochondrial cytochrome P-450. In the present study, paraquat inhibited the biosynthesis of aldosterone from 18-hydroxycorticosterone by mitochondria from duck adult adrenal gland, under aerobic conditions. Since paraquat did not induce any change in the absorption spectrum of highly purified cytochrome P-450 11 beta, the possibility of a displacement of steroid by the drug is ruled out. Moreover, paraquat did not affect oxidative phosphorylating chain nor did it alter by itself the chemical structure of 18-hydroxycorticosterone. In our conditions, the inhibitory role of paraquat seems restricted to a capture of electrons from reduced cytochrome P-450. Under the same conditions metopirone and spironolactone, known to bind cytochrome P-450 11 beta at the steroid binding site, also inhibited the reaction. Altogether these results show that for aldosterone synthesis from 18-hydroxycorticosterone to take place, the steroid binding site on cytochrome P-450 must be accessible to 18-hydroxycorticosterone and that the cytochrome P-450 must be the direct donor of reducing equivalents. Hence, cytochrome P-450 appears as the final linking point between 18-hydroxycorticosterone and the reducing equivalents provided by NADPH.
Blanchouin-Emeric
N
N
Service de Biochimie, Faculté de Médecine Pitié-Salpétrière, Paris, France.
Defaye
G
G
Toury
R
R
Vonarx
V
V
Aupetit
B
B
D015069:18-Hydroxycorticosterone / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism*; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D003345:Corticosterone / Q000031:analogs & derivatives*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004372:Ducks; D007700:Kinetics; D008297:Male; D008797:Metyrapone / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D010084:Oxidation-Reduction; D010269:Paraquat / Q000494:pharmacology*; D012016:Reference Values; D013148:Spironolactone / Q000494:pharmacology
D000451:Mineralocorticoid Receptor Antagonists; D013148:Spironolactone; D000450:Aldosterone; D015069:18-Hydroxycorticosterone; D003577:Cytochrome P-450 Enzyme System; D010269:Paraquat; D003345:Corticosterone; D008797:Metyrapone