Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Frater, Yvonne; Brady, A.M.; Lock, Edward A.; Matteis, Federico De

doi:10.1007/bf01973305

Cited by 18 publications

(11 citation statements)

References 26 publications

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“…Griseofulvin, ethyl-DDC, and TMDQ are metabolized by CYP enzymes, leading to the formation of N-alkyl protoporphyrins which covalently bind to ferrochelatase enzyme and inactivate it (De Matteis and Marks 1996;Halpert et al 1994). Similar mechanisms are also suspected for AIA and ATMP (Frater et al 1993;De Matteis and Marks 1996). Especially ethyl-DDC is a highly potent ferrochelatase inhibitor and cellular heme depletor (Halpert et al 1994).…”

Section: Discussionmentioning

confidence: 94%

Regulation of CYP2A5 induction by porphyrinogenic agents in mouse primary hepatocytes

Salonpää

Kottari

Pelkonen

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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All cytochrome P450 (CYP) enzymes contain heme as a prosthetic group. In contrast to other CYP enzymes, murine CYP 2 A 5 is upregulated in vivo by several agents that disturb cellular heme balance. To test the hypothesis that porphyrinogenic agents have the common feature of being able to increase CYP 2 A 5 expression, mouse liver primary hepatocytes were exposed to various porphyrinogenic chemicals and changes in CYP 2 A 5 catalytic activity and levels of mRNA were monitored. Phenobarbital increased hepatic CYP 2 A 5-mediated coumarin 7-hydroxylase (COH) activity (13.2-fold) and the amount of CYP 2 A 5 steady-state mRNA (10.6-fold). Hepatocyte COH activity was increased also by the ferrochelatase inhibitor griseofulvin and the protoporphyrinogen oxidase inhibitor acifluorfen (about 9-fold induction). Of these inducers, only phenobarbital affected CYP 1 A 12 and CYP 2 B 10 expression. In contrast, many other porphyrinogenic agents such as cobalt, 2,2,4-trimethyl-1,2-dihydroquinoline (TMDQ), 1-[4-(3-acetyl-2,4,6-trimethylphenyl)-2,6-cyclohexanedionyl]-O-eth yl propionaldehyde oxime (ATMP), aminotriazole, and thioacetamide either decreased or had no effect on CYP 2 A 5. The increases in COH activity and CYP 2 A 5 mRNA were unaffected by combined treatment with the inducers and heme arginate, suggesting that heme is not a regulator of CYP 2 A 5 induction. Treatment with actinomycin D totally abolished both constitutive CYP 2 A 5 expression and its inducibility, suggesting that a transcriptional component is involved. These data suggest that, in mouse primary hepatocytes, CYP 2 A 5 induction is not a universal response to disturbed cellular heme biosynthesis.

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Section: Discussionmentioning

confidence: 94%

Regulation of CYP2A5 induction by porphyrinogenic agents in mouse primary hepatocytes

Salonpää

Kottari

Pelkonen

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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“…It would therefore be prudent when dealing with xenobiotics in which porphyrinogenicity depends upon interaction with P450 enzymes and N-alkylPP formation to supplement animal data with studies in human liver microsomes and cDNAexpressed individual P450 enzyme preparations. This would be particularly important where xenobiotics are shown to be porphyrinogenic due to the production of N-alkylPPs in the livers of some animal species but not others (Frater et al, 1993).…”

Section: Human P450 Sources Of N-alkylpp After Interaction With Xenobmentioning

confidence: 99%

“…In the case of xenobiotics, which owe their porphyrinogenicity to mechanism-based inactivation of selective P450 enzymes with formation of N-alkylPPs, the problem stems, in part, to differences in the P450 enzymes between animals and humans. This is a particular problem when a xenobiotic is found to be porphyrinogenic in one species but not in others (Frater et al, 1993). Therefore, an understanding of the human P450 enzymes targeted by these xenobiotics is required to establish whether porphyria elicited in animals is likely to occur in humans.…”

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confidence: 99%

Identification of Human Hepatic Cytochrome P450 Sources of N-alkylprotoporphyrin IX after Interaction with Porphyrinogenic Xenobiotics, Implications for Detection of Xenobiotic-Induced Porphyria in Humans

Lavigne

Nakatsu²,

Marks³

2002

Drug Metabolism and Disposition

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ABSTRACT:Porphyrinogenicity of certain xenobiotics depends upon mechanism-based inactivation of specific cytochrome P450 (P450) enzymes, followed by formation of N-alkylprotoporphyrin IX (N-alkylPP). Examination of the porphyrinogenicity of xenobiotics in animals and extrapolation of the results to humans is associated with ambiguity due, in part, to differences between P450 enzymes. The goal of this study was to develop an in vitro test for the detection of N-alkylPPs, produced in human liver after administration of xenobiotics found to be porphyrinogenic in animals. This goal was achieved using fluorometry to detect N-alkylPP formation following mechanism-based inactivation by porphyrinogenic xenobiotics of single cDNA-expressed human P450 enzymes in microsomes prepared from baculovirus-infected insect cells ( Xenobiotics which interfere with control of heme biosynthesis and allow porphyrins to accumulate are referred to as porphyrinogenic. The porphyrinogenic effects of several xenobiotics (e.g., TTMS 1 , 4-ethyl DDC, and AIA) depend on their ability to cause mechanismbased inactivation of P450 enzymes (Ortiz de Montellano et al., 1981a;Ortiz de Montellano and Grab, 1986; Oritz de Montellano and Mico, 1981c). These xenobiotics, upon selective P450 enzyme mediated biotransformation, form reactive intermediates at the P450 active site. The reactive intermediates interact with the heme moiety resulting in N-alkylation of a pyrrole ring (Marks et al., 1988;Ortiz de Montellano and Correia, 1995). P450 inactivation and dissociation of N-alkylheme is followed by loss of iron, yielding N-alkylprotoporphyrin IX (N-alkylPP), some of which are potent inhibitors of ferrochelatase (EC 4.99.1.1) (De Matteis et al., 1980;Cole et al., 1981). Ferrochelatase inhibition results in decreased heme production and less control over the rate-limiting enzyme aminolevulinic acid synthase (EC 2.3.1.37; aminolevulinic acid synthase). Increased aminolevulinic acid synthase activity results in porphyrin accumulation and porphyria (De Matteis and Marks, 1996). The N-alkylPP formed after mechanism-based inactivation of P450 by AIA, viz. N-AIAPP 2 , does not inhibit ferrochelatase. The porphyrinogenic effect of AIA is explained as follows: since P450 can be reconstituted after undergoing mechanism-based inactivation by AIA as a result of the exchange of the N-alkylated heme moiety (N-AIAPP) for a fresh heme molecule, AIA functions as a heme-destructive catalyst that depletes regulatory free heme (Ortiz de Montellano et al., 1985).The porphyrinogenicity of TTMS, 4-ethyl DDC, and AIA, has been shown in animals to be dependent on mechanism-based inactivation of specific P450 enzymes (Marks et al., 1988). Our previous in vivo studies have elucidated the important rat liver P450 enzymes responsible for N-alkylPP formation. CYP3A2 is the major source of Nvinylprotoporphyrin IX (N-vinylPP) after the administration of TTMS to rats whereas CYP2C11 is the major source of N-ethylprotoporphyrin IX (N-ethylPP) and N-AIAprotoporphyrin IX (N-AIAPP) after...

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“…In other laboratory species such as mice, rats and genetically engineered (ferrochelatase deficient) mice, such changes have been described as well after drug-treatment (Zaki et al, 1973;Matilla and Molland, 1974;Cantoni et al, 1983;Tutois et al, 1991;Frater et al, 1993;Smith et al, 1997). However, in a rat study carried out in our laboratory with the same drug candidate as used in the dog study, no lesions indicative for porphyria were observed.…”

Section: Discussionmentioning

confidence: 99%

“…Domestic animals mainly develop congenital and hereditary porphyria (With, 1980) whereas in laboratory animals (rats and mice) drug-induced porphyria have been described in literature (Matilla and Molland, 1974;Gralla et al, 1977;Cantoni et al, 1983;Frater et al, 1993;Smith, 1997). For dogs, information about experimentally induced porphyria is scarce and not of recent date (Stokvis, 1895;Zaki et al, 1973;Stejskal et al, 1975).…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Protoporphyria in Beagle Dogs

Putten¹,

Esch²,

Kamerman³

et al. 2005

Toxicol Pathol

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As part of regulatory safety testing program, a 13-week oral toxicity study with a new antipsychotic drug candidate was performed in beagle dogs. During this study, dark red/brown feces were recorded in treated dogs and increases in liver parameters (alanine aminotransferase, alkaline phosphatase, bilirubin) were measured biochemically. At the end of the study, livers of high-dose (50 mg/kg) animals were (mottled) dark brown, sometimes with pale foci. Histopathological examination of these livers showed dark globular pigment deposits in the hepatocellular cytoplasm and within the bile canaliculi. Varying numbers of inflammatory cell infiltrates were additionally present in association with the deposits. These pigment deposits showed birefringency with characteristic "Maltese Cross"-like structures under polarized light. Electronmicroscopy revealed the typical, so-called "sunburst" pattern with radiating double-lined crystalline structures. These morphologic characteristics strongly indicated at the presence of porphyrins, which was definitely confirmed biochemically. Published reports of drug-induced hepatic porphyria in dogs are rare. The possible underlying mechanism in the dog and man is discussed.

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Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Cited by 18 publications

References 26 publications

Regulation of CYP2A5 induction by porphyrinogenic agents in mouse primary hepatocytes

Regulation of CYP2A5 induction by porphyrinogenic agents in mouse primary hepatocytes

Identification of Human Hepatic Cytochrome P450 Sources of N-alkylprotoporphyrin IX after Interaction with Porphyrinogenic Xenobiotics, Implications for Detection of Xenobiotic-Induced Porphyria in Humans

Drug-Induced Protoporphyria in Beagle Dogs

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