Enzymatic metabolism of ergosterol by cytochrome p450scc to biologically active 17alpha,24-dihydroxyergosterol.
We demonstrate the metabolism of ergosterol by cytochrome P450scc in either a reconstituted system or isolated adrenal mitochondria. The major reaction product was identified as 17alpha,24-dihydroxyergosterol. Purified P450scc also generated hydroxyergosterol as a minor product, which is probably an intermediate in the synthesis of 17alpha,24-dihydroxyergosterol. In contrast to cholesterol and 7-dehydrocholesterol, cleavage of the ergosterol side chain was not observed. NMR analysis clearly located one hydroxyl group to C24, with evidence that the second hydroxyl group is at C17. 17alpha,24-Dihydroxyergosterol inhibited cell proliferation of HaCaT keratinocytes and melanoma cells. Thus, in comparison with cholesterol and 7-dehydrocholesterol, the 24-methyl group and the C22-C23 double bond of ergosterol prevent side chain cleavage by P450scc and change the enzyme's hydroxylase activity from C22 and C20, to C24 and C17, generating bioactive product.
Slominski
Andrzej
A
Department of Pathology and Laboratory Medicine, University of Tennessee, Health Science Center, Memphis, Tennessee 38163, USA. aslominski@utmem.edu
Semak
Igor
I
Zjawiony
Jordan
J
Wortsman
Jacobo
J
Gandy
Michael N
MN
Li
Jinghu
J
Zbytek
Blazej
B
Li
Wei
W
Tuckey
Robert C
RC
D000311:Adrenal Glands; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D004875:Ergosterol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D010840:Phytosterols / Q000378:metabolism; D013329:Structure-Activity Relationship
C507305:17,24-dihydroxyergosterol; D010840:Phytosterols; D002786:Cholesterol Side-Chain Cleavage Enzyme; D004875:Ergosterol