Suicidal destruction of cytochrome p-450 by ethynyl substituted compounds

Compounds containing a terminal carbon-carbon triple bond, ranging in structure from the 17α-ethynyl substituted contraceptive steroids to acetylene gas, when administered to rats cause a selective and rapid time dependent loss of up to 50% of hepatic cytochrome P-450. Cytochrome b5 is not affected. Metabolic activation of the acetylenic substituent by the phenobarbital inducible, NADPH dependent, mixed function oxidases results in the formation of a reactive species which alkylates one of the tetrapyrrole nitrogen atoms of heme to form a 1 : 1 covalent adduct. Either cytochrome P-450 destruction or the formation of N-alkylated porphyrins (green pigments) have been used to assess factors affecting the extent of metabolic activation of the acetylenic group in rats, man, and other laboratory species. The chemical identity of a number of green pigments have been resolved. Those formed from 1-octyne consist of the protoporphyrin IX ring of heme substituted with the saturated 2-oxo-octyl group. In contrast, reactive metabolites of 1-octyne trapped with N-acetylcysteine contain the unsaturated 3-oxo-octenyl substituent. Two independent routes of activation of terminal acetylenes have been described to account for these results. Both pathways can lead to cytochrome P-450 loss but only one, probably involving an oxirene intermediate, leads to green pigment formation.