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.
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.
McCluskey
S A
SA
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ont., Canada.
Riddick
D S
DS
Mackie
J E
JE
Kimmett
S M
SM
Whitney
R A
RA
Marks
G S
GS
D000818:Animals; D002642:Chick Embryo; D065607:Cytochrome P-450 Enzyme Inhibitors; D003997:Dicarbethoxydihydrocollidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D005294:Ferrochelatase / Q000037:antagonists & inhibitors*; D006418:Heme / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000494:pharmacology
D065607:Cytochrome P-450 Enzyme Inhibitors; C078953:4-nonyl-3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethylpyridine; C078954:4-dodecyl-3,5-diethoxycarbonyl-1,4-dihydro-2,6-dimethylpyridine; D006418:Heme; D003997:Dicarbethoxydihydrocollidine; D005294:Ferrochelatase; D015032:Zinc; D010634:Phenobarbital