N-Alkylprotoporphyrin IX formation in 3,5-dicarbethoxy-1,4-dihydrocollidine-treated rats. Transfer of the alkyl group from the substrate to the porphyrin.

Montellano, Paul R. Ortiz de; Beilan, Hal S.; Kunze, Kent L.

doi:10.1016/s0021-9258(19)69049-6

Cited by 100 publications

(14 citation statements)

References 27 publications

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“…One result that is difficult to rationalize by a mechanism other than formation of a nitrogen radical cation is the finding that the oxidation of 3,5-(bis)carbethoxy-2,6-dimethyl-4-alkyl-1,4-dihydropyridines results in transfer of the 4-alkyl group from the substrate to a nitrogen of the heme group. 119 This group transfer occurs when the dihydropyridine is oxidized within the P450 active site. However, when the reaction is catalyzed by liver microsomes the oxidation can also be mediated by trace metals outside of the P450 active site, in which case the 4-alkyl group can be detected as a free radical by spin trapping experiments.…”

Section: Heteroatom Oxidationmentioning

confidence: 99%

Oxidizing species in the mechanism of cytochrome P450

2002

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This review discusses the mechanisms of oxygen activation by cytochrome P450 enzymes, the possible catalytic roles of the various iron--oxygen species formed in the catalytic cycle, and progress in understanding the mechanisms of hydrocarbon hydroxylation, heteroatom oxidation, and olefin epoxidation. The focus of the review is on recent results, but earlier work is discussed as appropriate. The literature through to February 2002 is surveyed, and 175 referenced are cited.

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Section: Heteroatom Oxidationmentioning

confidence: 99%

Oxidizing species in the mechanism of cytochrome P450

2002

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“…One pathway involves the modification of the heme moiety to products that can dissociate from the protein; this is best exemplified by the formation of the well-documented green pigments that result from N-alkylation of the iron porphyrin apparently by reactive radical or cation radical metabolites of the substrate (for review see ref 4). In the case of 3,5-dicarbethoxy-2,6-dimethyl-4-ethyl-l,4-dihydropyridine (DDEP), it is thought that this process occurs by a one-electron oxidation of the nitrogen of DDEP by cytochrome P-450 to yield a radical cation intermediate that subsequently aromatizes and releases an ethyl radical (4)(5)(6), which ethylates the pyrrole nitrogen of the prosthetic heme moiety (5).…”

Section: Introductionmentioning

confidence: 99%

Covalent bonding of the prosthetic heme to protein: a potential mechanism for the suicide inactivation or activation of hemoproteins

Osawa

Pohl

1989

Chem. Res. Toxicol.

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In this perspective we have described a newly characterized pathway for the metabolism of the prosthetic heme of cytochrome P-450, which results in the formation of protein-bound adducts. This reaction occurs when the cytochrome P-450 metabolizes a variety of xenobiotics as well as endogenous compounds such as hydrogen peroxide and lipid hydroperoxides. It also takes place during the reactions catalyzed by other hemoproteins, such as myoglobin and hemoglobin. In the case of the reaction of ferrous myoglobin with BrCCl3, under single-turnover conditions, an intact heme moiety becomes covalently bound to an active-site amino acid. This covalently altered protein has significantly enhanced reductive activity compared to that of native myoglobin, as demonstrated by its rapid reduction of molecular oxygen and CCl4. It also is more rapidly proteolyzed than myoglobin. These findings may have relevance to the P-450 cytochromes in which suicide inactivation, destruction of the heme prosthetic group, and loss of the protein is observed. The activation of hemoproteins to heme-protein adducts may also have toxicological significance, perhaps in oxygen reperfusion injury in the myocardium as well as other tissues by enhancing the production of oxygen-derived radicals from molecular oxygen and lipid hydroperoxides. Clearly, further research in the characterization of heme-protein adducts is necessary before their importance in protein turnover and oxygen-induced injury can be determined.

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“…Administration of DMDQ to phenobarbital-pretreated rats results in the accumulation of a hepatic green pigment that can be extracted from liver homogenates with acidic methanol. This treatment esterifies the acid side chains of porphyrins and removes loosely bound iron (1,21). Extraction of the esterified porphyrin pigment into methylene chloride, addition of zinc acetate to convert free porphyrins to their 0 Ethoxycoumarin deethylation was assayed as described in the experimental section by removing aliquots of the enzyme mixture after incubation for 0 or 5 min with DMDQ.…”

Section: Resultsmentioning

confidence: 99%

“…Pregnenolone-16a-carbonitrile was a gift from G.D. Searle & Co. (Skokie, IL). The preparation of authentic IV-methylprotoporphyrin IX, N-ethylprotoporphyrin IX, and DDEP has been reported (1,2,21). 1H NMR spectra were recorded in deuteriated chloroform.…”

Section: Methodsmentioning

confidence: 99%

2,2-Dialkyl-1,2-dihydroquinolines: cytochrome P 450 catalyzed N-alkylporphyrin formation, ferrochelatase inhibition, and induction of 5-aminolevulinic acid synthase activity

Lukton¹,

Mackie²,

Lee³

et al. 1988

Chem. Res. Toxicol.

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Incubation of 2,4-diethyl-1,2-dihydro-2-methylquinoline (DMDQ) with hepatic microsomes from rats pretreated with phenobarbital, 3-methylcholanthrene, pregnenolone-16 alpha-carbonitrile, or dexamethasone results in minor loss of the cytochrome P-450 chromophore and accumulation of a hepatic pigment. The hepatic pigment consists of the four regioisomers of N-ethylprotoporphyrin IX and minor amounts of the corresponding N-methyl regioisomers. Exposure of chick embryo liver cells to DMDQ results in inhibition of their ferrochelatase activity, induction of their 5-aminolevulinic acid synthase activity, and accumulation of protoporphyrin IX. 1,2-Dihydro-2,2,4-trimethylquinoline (TMDQ) causes negligible loss of cytochrome P-450 in rat liver microsomes but in vivo still produces the four N-methylprotoporphyrin IX regioisomers in low yield. Furthermore, it inhibits ferrochelatase activity, elevates 5-aminolevulinic acid synthase activity, and causes protoporphyrin IX accumulation in cultured chick embryo hepatocytes. One-electron oxidation of the 2,2-dialkyl-1,2-dihydroquinolines to radical cations is postulated to result in N-alkylation of the prosthetic heme group of cytochrome P-450. The N-alkylprotoporphyrins IX thus formed are potent inhibitors of ferrochelatase. Inhibition of ferrochelatase causes the induction of 5-aminolevulinic acid synthase and the accumulation of protoporphyrin IX. Heme alkylation and ferrochelatase inhibition may be generally associated with substrates that are subject to cytochrome P-450 mediated oxidative extrusion of alkyl radicals.

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N-Alkylprotoporphyrin IX formation in 3,5-dicarbethoxy-1,4-dihydrocollidine-treated rats. Transfer of the alkyl group from the substrate to the porphyrin.

Cited by 100 publications

References 27 publications

Oxidizing species in the mechanism of cytochrome P450

Oxidizing species in the mechanism of cytochrome P450

Covalent bonding of the prosthetic heme to protein: a potential mechanism for the suicide inactivation or activation of hemoproteins

2,2-Dialkyl-1,2-dihydroquinolines: cytochrome P 450 catalyzed N-alkylporphyrin formation, ferrochelatase inhibition, and induction of 5-aminolevulinic acid synthase activity

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