Specific accumulation of 17 alpha-hydroxyprogesterone in microsomal membranes during the process of cytochrome P-450(C-17)-catalysed androgen biosynthesis. A dynamic study of intermediate formation and turnover.
A complete dynamic analysis of cytochrome P-450(C-17)-catalysed androgen biosynthesis from a single dose of progesterone and 17 alpha-hydroxyprogesterone in a double-label double-substrate experiment was performed in order to elucidate the controversial intermediacy of 17 alpha-hydroxyprogesterone. Label distribution within the steroid fractions as well as in the membrane and buffer compartments yields direct evidence that the endogenously formed 17 alpha-hydroxyprogesterone (which is in an 'intermediate state') accumulates to a higher degree in microsomal membranes than does the exogenously added 17 alpha-hydroxyprogesterone (which is in a 'substrate state') under certain conditions. It is also demonstrated that endogenously formed 17 alpha-hydroxyprogesterone may partly leave the membrane compartment (in terms of a 'leakage' or 'overflow' phenomenon) and is then able to equilibrate with the pool of exogenously added 17 alpha-hydroxyprogesterone. Since only the label distribution in the membrane-associated (but not always in the aqueous) 17 alpha-hydroxyprogesterone pool corresponds to the label distribution in the androgen fraction, it is concluded that only the membrane-associated 17 alpha-hydroxyprogesterone pool is directly accessible to cytochrome P-450(C-17)-catalysed conversion into androgens.
Kühn-Velten
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N
Institut für Physiologische Chemie II, Universität Düsseldorf, Federal Republic of Germany.
Lessmann
M
M
Förster
M E
ME
Staib
W
W
D019326:17-alpha-Hydroxyprogesterone; D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006908:Hydroxyprogesterones / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008954:Models, Biological; D011374:Progesterone / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013737:Testis / Q000378:metabolism*; D014316:Tritium
D000728:Androgens; D002250:Carbon Radioisotopes; D006908:Hydroxyprogesterones; D014316:Tritium; D011374:Progesterone; D019326:17-alpha-Hydroxyprogesterone; D003577:Cytochrome P-450 Enzyme System