Inactivation of cytochrome <i>P</i>‐450 and production of <i>N</i>‐alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines

Matteis, Federico De; Hollands, C.; Gibbs, Anthony H.; De, Nettleton; Rizzardini, Milena

doi:10.1016/0014-5793(82)81212-x

Cited by 39 publications

(20 citation statements)

References 32 publications

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“…In general the yield of N-ethylprotoporphyrin after 4-ethyl-DDC administration was greater in rats pretreated with inducers than in control rats. This is in agreement with previous findings obtained in intact rats and in isolated hepatocytes (Coffman et al, 1982;De Matteis et al, 1982a). In addition we now find that -the isomeric composition of the alkylated porphyrins depends on the type of cytochrome P-450 predominating at the time of treatment.…”

Section: Treatmentsupporting

confidence: 94%

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N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

Matteis¹,

Gibbs²,

Hollands³

1983

Biochemical Journal

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1. 3,5-Diethoxycarbonyl-4-ethyl-1,4-dihydro-2,6-dimethylpyridine (4-ethyl-DDC) gives rise to N-ethylprotoporphyrin in the liver of rats by donating its 4-ethyl group to one of the pyrrole nitrogen atoms of haem. Four structural isomers are obtained, depending on which pyrrole nitrogen is alkylated. 2. When rats are pretreated with an inducer of cytochrome P-450, the production of N-ethylprotoporphyrin caused by 4-ethyl-DDC is greater, both in the whole animal and in hepatocytes incubated with the drug in vitro. 3. Pre-incubation of hepatocytes with 2-allyl-2-isopropylacetamide decreases the yield of N-ethylprotoporphyrin due to 4-ethyl-DDC, an effect largely reversed by adding exogenous haem. 4. The isomeric composition of N-ethylprotoporphyrin produced in vivo and in vitro depends on the cytochrome P-450 isoenzyme that predominates at the time of treatment, suggesting a role for the apo-cytochrome in directing alkylation on to one of the pyrrole nitrogens.

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Section: Treatmentsupporting

confidence: 94%

“…Viability (Trypan Blue exclusion) was 88-94% at the beginning of the incubation. The methods used for incubation of hepatocytes, extraction and estimation of N-alkylated porphyrins and assay of their inhibitory activity in vitro towards protohaem ferro-lyase (ferrochelatase) have all been described previously (De Matteis et al, 1982a).…”

Section: Ch2mentioning

confidence: 99%

N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

Matteis¹,

Gibbs²,

Hollands³

1983

Biochemical Journal

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“…More direct evidence for suicidal metabolism of ATMP by liver cytochrome P450 is still required. However, it is interesting to note that in the case of DDC, where a suicidal mechanism is supported by more direct evidence from four different laboratories (Augusto et al 1982;Coffman et al 1982;De Matteis et al 1982;Marks et al 1985), compound SKF 525-A has long been known to prevent the induction of porphyria and the inhibition of ferrochelatase (De Matteis et al 1973), as well as the drug-dependent accumulation of N-methyl protoporphyrin in the liver (Tephly et al 1980). The time course and dose-response experiments of Figs.…”

Section: Discussionmentioning

confidence: 94%

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Frater

Brady²,

Lock³

et al. 1993

Arch Toxicol

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1-[4-(3-Acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-eth yl propionaldehyde oxime (for short ATMP) is a novel porphyrogenic agent causing hepatic protoporphyria in the mouse. Mice given a single dose of the drug showed 24 h later a 70% inhibition of liver ferrochelatase and marked accumulation of protoporphyrin. These changes were not seen in similarly treated rats, guinea pigs, hamsters or chick embryos. A green pigment was isolated from the liver of mice treated with ATMP and identified by its electronic absorption spectrum and chromatographic properties on HPLC as N-methyl protoporphyrin. The ATMP pigment markedly inhibited the enzyme ferrochelatase in vitro, thus supporting its identification as N-methyl protoporphyrin. Two inhibitors of liver cytochrome P450, compound SKF 525-A and piperonyl butoxide, when given before ATMP, afforded protection against ATMP-induced porphyria and production of N-methyl protoporphyrin, suggesting a role of cytochrome P450 in the induction of the metabolic disorder. The most likely interpretation for these findings is therefore that ATMP is metabolized in the mouse to a reactive species, which in turn alkylates the haem moiety of liver cytochrome P450, thus producing N-methyl protoporphyrin. This inhibits ferrochelatase and, as a secondary response, protoporphyrin accumulates. This pathway of metabolism to the postulated reactive metabolite presumably does not occur to a significant extent in the other species examined and hence is the likely basis for the species difference in protoporphyria.

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“…From the numerous results published on the aromatization of Hantzsch 1,4-DHP (excluding the papers dealing with microwave-mediated experiments) the following rules can be established ( Scheme 3 ): Heterocycles bearing an aryl (or heteroaryl) group in position 4 always undergo a dehydrogenation process [ 18 ]; Heterocycles bearing a linear alkyl group in position 4 undergo a dehydrogenation process, except in vivo where dealkylation occurs and is accompanied by inhibition of cytochrome P-450 [ 8 , 18 , 19 , 20 ]; Heterocycles bearing a benzylic or secondary alkyl group in position 4 undergo a dealkylation process except when the oxidizing species is sulfur [ 21 ] or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone [ 22 ]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Aromatization of Hantzsch 1,4-Dihydropyridines under Microwave Irradiation. An Overview

Eynde

Mayence

2003

Molecules

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Inactivation of cytochrome P‐450 and production of N‐alkylated porphyrins caused in isolated hepatocytes by substituted dihydropyridines

Cited by 39 publications

References 32 publications

N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

N-alkylation of the haem moiety of cytochrome P-450 caused by substituted dihydropyridines. Preferential attack of different pyrrole nitrogen atoms after induction of various cytochrome P-450 isoenzymes

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Synthesis and Aromatization of Hantzsch 1,4-Dihydropyridines under Microwave Irradiation. An Overview

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