Abstract

Several xenobiotics caused hepatic porphyrin accumulation through mechanism-based inactivation of cytochrome P450(P450) and heme alkylation. Loss of iron from the alkylated heme results in formation of an N-alkylporphyrin, which is a potent inhibitor of ferrochelatase. N-Vinylprotoporphyrin IX (N-vinylPP) was identified in chick embryo liver after in ovo administration of 3-[(arylthio)ethyl]sydnone (TTMS). Pretreatment of chick embryos with beta-naphthoflavone, which causes a 90-fold increase in P450 1A levels, did not increase the formation of N-vinylPP after TTMS administration, showing that the heme moiety of P450 1A does not contribute to the formation of N-vinylPP. Increased amounts of N-vinylPP were isolated from dexamethasone-, phenobarbital-, and glutethimide-pretreated chick embryos, and it is possible that P450 2H and/or a P450 3A-like isozyme contributes to the formation of N-vinylPP. The ring B-substituted (NB) regioisomer of N-vinylPP constituted the lowest percentage of the total regioisomers (9-13%) in untreated and drug-induced chick embryos, thus supporting the concept that ring B of heme is occluded by a protein residue in the P450 active site. Previously, the finding that the NB regioisomer of N-ethylprotoporphyrin IX had one fifth the potency of the ring A-substituted (NA) regioisomer as a ferrochelatase inhibitor led to a proposal that an A-C ring tilt was important in N-alkylprotoporphyrins for ferrochelatase inhibition. The finding in the present study that the NA and NB regioisomers of N-vinylPP are equipotent does not support the above proposal. The ring C-substituted (NC) and ring D-substituted (ND) regioisomers of N-vinylPP had low potency.