Strain and sex differences in the response of mice to drugs that induce protoporphyria: Role of porphyrin biosynthesis and removal

Holley, Anne; King, Laurence J.; Gibbs, Anthony H.; Matteis, Federico De

doi:10.1002/jbt.2570050307

Cited by 14 publications

(20 citation statements)

References 22 publications

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“…The inhibitor has been isolated from the liver of ATMP-treated animals and characterized as an N-alkylated protoporphyrin, with inhibitory activity on ferrochelatase and chromatographic behaviour on HPLC indistinguishable from those of authentic N-methyl protoporphyrin. Both vinyl-and propionate-substituted ring isomers were present, but the former clearly predominated, as also reported for the isomeric composition of N-methyl protoporphyrin isolated after treatment with either DDC or GF (Holley et al 1990). …”

Section: Discussionmentioning

confidence: 52%

“…When subjected to HPLC in this system, the ATMP-derived green pigment afforded two peaks with retention times of 3.72 and 6.11 min, corresponding in retention time to the F1 and F2 components of N-methyl protoporphyrin (3.69 and 6.02 min). The F1 and F2 fractions of the ATMP pigment were estimated to be present in a 19 : 1 ratio, indicating a clear preponderance of the vinyl substituted ring isomers similarly to what reported for the isomeric composition of the DDC and GF-derived N-methyl protoporphyrin (Holley et al 1990). …”

Section: Isolation and Characterization Of An Atmp-induced Green Pigmentmentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 52%

Section: Isolation and Characterization Of An Atmp-induced Green Pigmentmentioning

confidence: 97%

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Frater

Brady²,

Lock³

et al. 1993

Arch Toxicol

Self Cite

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“…5). The subsequent loss of haem results in a feedback upregulation of hepatic ALAS1 82,83. Stimulation of this enzyme drives increased haem synthesis compounding the inhibition of ferrochelatase and adding to the subsequent hepatic accumulation of porphyrin.…”

Section: Hepatic Tumours In Rodents Caused By Porphyria-inducing Chemmentioning

confidence: 99%

“…While some of these chemicals appear to induce porphyria irrespective of animal species, others show distinct strain, species and sex differences in sensitivity, with griseofulvin being more toxic to male than female mouse liver, and tralkoxidim being a potent porphyrogen in the mouse but not in the rat or hamster 83,95,99,100. Similarly an antiepileptic, synaptic vesicle 2a (SV2a) ligand, drug candidate was found to form a CYP mediated N -alkylprotoporphyrin derivative that inhibited ferrochelatase in the dog but not in the rat nor in human hepatocytes in vitro (Fig.…”

Section: Hepatic Tumours In Rodents Caused By Porphyria-inducing Chemmentioning

confidence: 99%

The association between chemical-induced porphyria and hepatic cancer

Smith

Foster²

2018

Toxicology Research

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The haem biosynthetic pathway is of fundamental importance for cellular metabolism both for the erythroid and nonerythroid tissues. There are several genetic variants of the pathway in the human population that cause dysfunction of one or other of the enzymes resulting in porphyrias of varying severity. Serious chronic hepatic and systemic diseases may result. Some of these can be precipitated by exposure to drugs including hormones, barbiturates and antibiotics, as well as alcohol and particular chlorinated aromatic chemicals. In experimental animals some of the steps of this pathway can also be severely disrupted by a variety of environmental chemicals, potential drugs and pesticides, especially in the liver, leading to the accumulation of uroporphyrins derived from the intermediate uroporphyrinogens or protoporphyrin IX, the immediate precursor of haem. With some of these chemicals this also leads to cholestasis and liver cell injury and eventually hepatic tumours. The review evaluates the available evidence linking hepatic porphyria with carcinogenesis in naturally occurring human genetic conditions and in chemically-induced porphyrias in laboratory animals. The existing data showing gender, strain, and species differences in sensitivity to the chemical-induced porphyrias, liver injury and liver tumours are discussed and the role that transgenically altered mouse models have played in defining the varying mechanisms. Finally, the review proposes a novel, unifying hypothesis linking the hepatotoxicity induced by the accumulation of various porphyrins, with the increased risk of developing hepatic cancer as a long term consequence.

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“…Hepatic ferrochelatase activities would be expected to be decreased by Ͼ90% in both Fech mice and those treated with griseofulvin for 3 weeks. 9,54,55 Despite equivalent levels of hepatic protoporphyrin and cholestatic injury in the two models there was a marked stimulation of cytochrome P450 isoforms, Hmox1 and Alas1 expression after drug treatment that was not seen in the mutant mouse ( Figure 7). 17,38 This induction of Alas1 and Hmox1 was much greater than the modest change observed with the phenobarbital-like CAR agonist TCPOBOP.…”

Section: Comparison With Griseofulvin Protoporphyriamentioning

confidence: 99%

Hepatic Gene Expression in Protoporphyic Fech Mice Is Associated with Cholestatic Injury but Not a Marked Depletion of the Heme Regulatory Pool

Davies

Schuurman

Barker

et al. 2005

The American Journal of Pathology

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BALB/c Fech m1Pas mice have a mutated ferrochelatase gene resulting in protoporphyria that models the hepatic injury occurring sporadically in human erythropoietic protoporphyria. We used this mouse model to study the development of the injury and to compare the dysfunction of heme synthesis with hepatic gene expression of liver metabolism, oxidative stress, and cellular injury/inflammation. From an early age expression of total cytochrome P450 and many of its isoforms was significantly lower than in wild-type mice. However, despite massive accumulation of protoporphyrin in the liver, expression of the main genes controlling heme synthesis and catabolism Heme is vital to the transport and utilization of oxygen in oxidative and signaling pathways. A large proportion of heme usage in the liver is accounted for by cytochrome P450 isoforms, many of which are associated with drug metabolism. In the final step of heme synthesis ferrous iron is inserted into the precursor porphyrin protoporphyrin IX by the mitochondrial enzyme ferrochelatase. The structure and regulation of ferrochelatase have been extensively studied.

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Strain and sex differences in the response of mice to drugs that induce protoporphyria: Role of porphyrin biosynthesis and removal

Cited by 14 publications

References 22 publications

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

The association between chemical-induced porphyria and hepatic cancer

Hepatic Gene Expression in Protoporphyic Fech Mice Is Associated with Cholestatic Injury but Not a Marked Depletion of the Heme Regulatory Pool

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