Evidence for the stereoselective inhibition of chick embryo hepatic ferrochelatase by N-alkylated porphyrins.
3,5-Diethoxycarbonyl-1,4-dihydro-2,6-dimethyl-4-ethylpyridine and its 4-propyl analogue were administered to phenobarbital-pretreated rats. The N-alkylprotoporphyrins (N-alkylPPs) that were isolated from rat livers, viz., N-ethylPP and N-propylPP, were found to have greater ferrochelatase-inhibitory potency than the corresponding synthetic N-alkylPPs. The N-ethylPP that was isolated from rat liver was found to contain 72% of the NB plus NA regioisomers, whereas synthetic N-ethylPP contained 40% of the NB plus NA regioisomers. In contrast, the N-propylPP that was isolated from rat liver contained the same amount of the NB/A regioisomer(s) as synthetic N-propylPP (33%). The NB plus NA regioisomers of N-ethylPP and the NB/A regioisomer(s) of N-propylPP that were isolated from rat liver were found to be significantly more potent than the corresponding synthetic regioisomers. We conclude that 1) the ferrochelatase-inhibitory potency of N-ethylPP that is isolated from rat liver is greater than that of synthetic N-ethylPP, due to differences in both regioisomer composition and the inhibitory potency of the NB plus NA regioisomers and stereoisomers, and 2) the ferrochelatase-inhibitory potency of N-propylPP that is isolated from rat liver is greater than that of synthetic N-propylPP, due solely to the difference in the ferrochelatase-inhibitory potency of the NB/A regioisomer(s) and stereoisomers. From the enhanced ferrochelatase-inhibitory potency of the NB plus NA regioisomers of N-ethylPP and the NB/A regioisomer(s) of N-propylPP that were isolated from rat liver, relative to the corresponding synthetic N-alkyllPP regioisomers, it was inferred that 2- and 4-vinyl substituents located on pyrrole rings A and B contribute to the optimal binding of N-alkylPPs to the ferrochelatase active site.
McCluskey
S A
SA
Department of Pharmacology, Queen's University, Kingston, Ontario, Canada.
Whitney
R A
RA
Marks
G S
GS
D000478:Alkylation; D000818:Animals; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D002942:Circular Dichroism; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D008190:Lyases / Q000037:antagonists & inhibitors*; D010634:Phenobarbital / Q000494:pharmacology; D011166:Porphyrins / Q000096:biosynthesis / Q000138:chemical synthesis / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D011166:Porphyrins; D008190:Lyases; D005294:Ferrochelatase; D010634:Phenobarbital