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  • Title: 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.
    Author: McCluskey SA, Marks GS, Sutherland EP, Jacobsen N, Ortiz de Montellano PR.
    Journal: Mol Pharmacol; 1986 Oct; 30(4):352-7. PubMed ID: 3762522.
    Abstract:
    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.
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