Self-catalyzed destruction of cytochrome P-450: covalent binding of ethynyl sterols to prosthetic heme.
The hepatic pigment accumulated as a consequence of the self-catalyzed destruction of cytochrome P-450 by norethisterone (17-hydroxy-19-nor-17 alpha-pregn-4-en-20-yn-3-one), after acidic methylation and purification, consists of two virtually identical, probably isomeric, porphyrins. Radiolabeled norethisterone is incorporated into both porphyrin products. The major of the two porphyrins exhibits a mass spectrometric molecular ion exactly equivalent to the sum of norethisterone and dimethylprotoporphyrin IX, less two hydrogen atoms: unequivocably demonstrating covalent association of the sterol with this porphyrin in a 1:1 ratio. Cytochrome P-450 is therefore destroyed by self-catalyzed addition of norethisterone to its heme prosthetic group. Cytochrome P-450 is also destroyed by norgestrel (13-ethyl-17-hydroxyl-18, 19-dinor-17 alpha-pregn-4-en-20-yn-3-one) and by 1-ethynylcyclohexanol but not by 17-hydroxy-19-nor-17alpha-pregn-4,20-dien-3-one. The destructive potential is thus clearly a property of the propargylic alcohol function. A mechanism involving enzymatic oxidation of the triple bond is postulated.
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009640:Norethindrone / Q000494:pharmacology*; D010860:Pigments, Biological / Q000378:metabolism; D051381:Rats
D010860:Pigments, Biological; D003577:Cytochrome P-450 Enzyme System; D009640:Norethindrone