Ferrochelatase-inhibitory activity and N-alkylprotoporphyrin formation with analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) containing extended 4-alkyl groups: implications for the active site of ferrochelatase.
The ferrochelatase-inhibitory activity, porphyrin-inducing activity, and cytochrome P-450- and heme-destructive effects of a variety of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were studied in chick embryo liver cells. The ferrochelatase-inhibitory activity of the 4-butyl, 4-pentyl, 4-hexyl, and 4-cyclopropylmethyl analogues of DDC was considered to be due to the formation of the corresponding N-alkylporphyrins. These N-alkylporphyrins were isolated from the livers of phenobarbital-pretreated rats following administration of the corresponding DDC analogues. The 4-isobutyl analogue did not have ferrochelatase-inhibitory activity despite its ability to cause formation of an N-isobutylporphyrin in rat liver. The 4-chloromethyl analogue of DDC inhibited ferrochelatase activity. The inability to isolate an N-alkylporphyrin from rat liver with this analogue may be due to its lability. The porphyrin-inducing activity of these analogues depended on their ferrochelatase-inhibitory potency and lipophilicity. The DDC analogues caused cytochrome P-450 and heme destruction. The relative ferrochelatase-inhibitory activity of the DDC analogues has implications for a postulated model of the binding of porphyrins in the ferrochelatase active site.
D000478:Alkylation; D000818:Animals; D001665:Binding Sites; D002642:Chick Embryo; D065607:Cytochrome P-450 Enzyme Inhibitors; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D006418:Heme / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008190:Lyases / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D011524:Protoporphyrins / Q000096:biosynthesis; D011725:Pyridines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D065607:Cytochrome P-450 Enzyme Inhibitors; D011524:Protoporphyrins; D011725:Pyridines; D006418:Heme; D003997:Dicarbethoxydihydrocollidine; D008190:Lyases; D005294:Ferrochelatase