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Inactivation of Cytochrome P450 and Inhibition of Ferrochelatase by Analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine With 4-nonyl and 4-dodecyl Substituents

Inactivation of Cytochrome P450 and Inhibition of Ferrochelatase by Analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine With 4-nonyl and 4-dodecyl Substituents

S A McCluskey, D S Riddick, J E Mackie, S M Kimmett, R A Whitney, G S Marks

Can J Physiol Pharmacol. 1992 Aug;70(8):1069-74.

PMID: 1473038

Abstract:

Cytochrome P450- and heme-destructive effects of the 4-nonyl and 4-dodecyl analogues of 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) were determined using hepatic microsomal preparations obtained from untreated, beta-naphthoflavone-treated, and phenobarbital-treated chick embryos. The 4-nonyl analogue of DDC was less efficacious than 4-ethyl DDC and 4-hexyl DDC, but more efficacious than 4-dodecyl DDC with respect to cytochrome P450-destructive activity. In all hepatic microsomal preparations, cytochrome P450 destruction by 4-nonyl DDC was accompanied by loss of microsomal heme. In contrast, 4-dodecyl DDC caused loss of heme only in hepatic microsomal preparations obtained from phenobarbital-treated chick embryos. The ability of 4-nonyl DDC and 4-dodecyl DDC to lower ferrochelatase activity was compared with that of 4-ethyl DDC and 4-hexyl DDC in cultured chick embryo hepatocytes. As the length of the 4-alkyl group was increased, the ferrochelatase-lowering efficacy and potency of the DDC analogue decreased. The 4-dodecyl DDC analogue was unable to lower ferrochelatase activity, which accorded with the finding that the administration of 4-dodecyl DDC to phenobarbital-treated rats did not lead to the accumulation of an N-alkylprotoporphyrin. The ability of 4-nonyl DDC to lower ferrochelatase activity was attributed to the formation of N-nonylprotoporphyrin IX following the administration of 4-nonyl DDC to phenobarbital-treated rats.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP108758	2,4,6-Trimethylpyridine		108-75-8	Price

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