Differential inhibition of hepatic ferrochelatase by regioisomers of N- butyl-, N-pentyl-, N-hexyl-, and N-isobutylprotoporphyrin IX

SA McCluskey, GS Marks, RA Whitney and PR Ortiz de Montellano

Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario.

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.

Volume 34, Issue 1, pp. 80-86, 07/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics

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