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Inactivation of cytochrome P ‐450 and production of N ‐alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines
Author(s) -
de Matteis F.,
Hollands C.,
Gibbs A.H.,
de Sa N.,
Rizzardini M.
Publication year - 1982
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(82)81212-x
Subject(s) - section (typography) , chemistry , alkylation , pharmacology , toxicology , biochemistry , biology , computer science , operating system , catalysis
Drugs with unsaturated side chains and certain dihydropyridines both convert liver haem into Nalkylated porphyrins, but the underlying mechanisms differ in the two cases. With unsaturated drugs, for example 2-allyl-2-isopropylacetamide (AIA), a monooxygenated derivative of the drug becomes bound [l] onto one of the pyrrole nitrogen atoms [2-41 of liver haem; whereas with 3,5diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC) only the 4-methyl substituent of the drug is transferred onto the pyrrole nitrogen atom [5-71 and the product, N-methyl protoporphyrin, is a powerful inhibitor of ferrochelatase (EC 4.99.1.1) [8,9]. There is strong evidence that the N-alkylated porphyrins produced by unsaturated compounds all originate from the haem of cytochrome P-450 [ 10-121, but it is less clear from which pool of hepatic haem N-methyl protoporphyrin originates after treatment with DDC; and the detailed mechanism of the transmethylation reaction involved has not yet been elucidated. The aim of the experiments described in this paper has been to clarify wether N-methyl protoporphyrin originates from the haem of cytochrome P450 and whether exogenous haem can be utilized