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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

SA McCluskey, GS Marks, EP Sutherland, N Jacobsen and PR Ortiz de Montellano

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.

Volume 30, Issue 4, pp. 352-357, 10/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics




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