Differential inhibition of hepatic ferrochelatase by regioisomers of N-butyl-, N-pentyl-, N-hexyl-, and N-isobutylprotoporphyrin IX.
A series of analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC), viz. 4-butyl DDC, 4-pentyl DDC, and 4-hexyl DDC was administered to phenobarbital-pretreated rats. The N-alkylprotoporphyrins (N-alkylPP) isolated from the rat livers were separated into regioisomers by means of high performance liquid chromatography; the NB or NA (NB/A) regioisomers constituted 19-26% of the total regioisomers. Considerable ferrochelatase-inhibitory activity was found in the NB/A regioisomers; the NC or ND (NC/D) regioisomers had little ferrochelatase-inhibitory activity. These findings supported the idea that the ferrochelatase active site could accommodate alkyl groups larger than methyl only if they were present on the nitrogens of the A or B pyrrole rings of the N-alkylPP. The inactivity of 4-isobutyl DDC as a ferrochelatase-lowering agent was investigated. After injection of 4-isobutyl-DDC into phenobarbital-pretreated rats, N-isobutylPP was isolated from the rat livers and separated into its regioisomers; the NB/A regioisomer constituted 3.8% of the total regioisomers. The NB/A regioisomer was found to have appreciable ferrochelatase-inhibitory activity whereas the NC/D regioisomer was inactive. The inactivity of 4-isobutyl-DDC as a ferrochelatase-lowering agent was attributed to the small amount of NB/A regioisomer present in the N-isobutylPP regioisomer mixture.
McCluskey
S A
SA
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario.
Marks
G S
GS
Whitney
R A
RA
Ortiz de Montellano
P R
PR
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000032:analysis; D008099:Liver / Q000201:enzymology*; D008190:Lyases / Q000037:antagonists & inhibitors*; D008297:Male; D011166:Porphyrins / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004095:Dihydropyridines; D007527:Isoenzymes; D011166:Porphyrins; D011524:Protoporphyrins; D003997:Dicarbethoxydihydrocollidine; D003577:Cytochrome P-450 Enzyme System; D008190:Lyases; D005294:Ferrochelatase