Isolation of two <i>N</i>-monosubstituted protoporphyrins, bearing either the whole drug or a methyl group on the pyrrole nitrogen atom, from liver of mice given griseofulvin

Holley, Anne; Frater, Yvonne; Gibbs, Anthony H.; Matteis, Federico De; Lamb, John H.; Farmer, Peter B.; Naylor, Stephen

doi:10.1042/bj2740843

Cited by 24 publications

(25 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…M17 is a GSF-PPIX adduct that has been proposed previously [32, 33]. The fragment ions of M17 perfectly matched the structure of GSF-PPIX (Fig.…”

Section: Resultssupporting

confidence: 70%

“…6F). GSF-PPIX is the precursor of N -methyl PPIX [32, 34, 35], which can strongly inhibit FECH and result in PPIX accumulation.…”

Section: Resultsmentioning

confidence: 99%

“…Our data suggest that GSF-induced liver injury initiated from GSF bioactivation, which produces GSF-PPIX adducts and N -methyl PPIX. N -methyl PPIX strongly inhibits the conversion of PPIX to heme and leads to PPIX accumulation [32, 34, 35]. Reactive metabolites of GSF and high levels of PPIX can directly cause liver damage [26, 36].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A metabolomic perspective of griseofulvin-induced liver injury in mice

Liu

Yan

Sachar

et al. 2015

Biochemical Pharmacology

View full text Add to dashboard Cite

Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contributed to the formation of GSF-PPIX, GSF-GSH and GSF-proline adducts. GSF-PPIX is the precursor of N-methyl PPIX. A six-fold increase of N-methyl PPIX was observed in the liver of mice after GSF treatment. N-methyl PPIX strongly inhibits ferrochelatase, the enzyme that converts PPIX to heme, and leads to PPIX accumulation. Excessive PPIX in the liver results in bile duct blockage and disturbs bile acid homeostasis. The accumulation of GSH in the liver was likely due to Nrf2-mediated upregulation of GSH synthesis. In summary, this study provides the biochemical basis of GSF-induced liver injury that can be used to understand the pathophysiology of EPP-associated liver injury in humans.

show abstract

“…M17 is a GSF-PPIX adduct that has been proposed previously [32, 33]. The fragment ions of M17 perfectly matched the structure of GSF-PPIX (Fig.…”

Section: Resultssupporting

confidence: 70%

“…6F). GSF-PPIX is the precursor of N -methyl PPIX [32, 34, 35], which can strongly inhibit FECH and result in PPIX accumulation.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A metabolomic perspective of griseofulvin-induced liver injury in mice

Liu

Yan

Sachar

et al. 2015

Biochemical Pharmacology

View full text Add to dashboard Cite

show abstract

“…This inhibitory pigment, which explains the inhibition of ferrochelatase and the accumulation of protoporphyrin induced by DDC and GF, has been identified as N-methyl protoporphyrin (De Matteis et al 1980b;Ortiz De Montellano et al 1981a;Tephly et al 1981), the N-methyl group originating from the drug both in the case of DDC (De Matteis et al 1981;Ortiz de Montellano et al 1981 b;Tephly et al 1981) and possibly also with GF (Holley et al 1991), during metabolism of these drugs by cytochrome P450. Experiments were therefore carried out to investigate whether a ferrochelatase inhibitory pigment was also present in excess in the liver of ATMP-treated mice and whether a role of cytochrome P450 could also be demonstrated in the induction of protoporphyria by ATMP.…”

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

confidence: 96%

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Frater

Brady²,

Lock³

et al. 1993

Arch Toxicol

View full text Add to dashboard Cite

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.

show abstract

“…The antifungal drug griseofulvin, used for the treatment of dermatomycosis for more than 30 years, 11 generates N-methyl-protoporphyrin in liver cells, 12,13 which inhibits ferrochelatase activity. This leads to an induction of delta aminolevulinic acid synthase, the rate-limiting enzyme in the pathway, and PP accumulation as seen in EPP.…”

mentioning

confidence: 99%

Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria

et al. 2002

View full text Add to dashboard Cite

Hepatic complications in erythropoietic protoporphyria (EPP) have been attributed to toxic actions of accumulated protoporphyrin (PP). PP can only be removed via the bile but transport systems involved have not been defined. The aim of this study was to gain insight in the mode of biliary PP excretion, with emphasis on the potential contribution of the Mdr1 P-glycoprotein export pump and biliary lipids as PP carriers. Control mice and mice homozygous for Mdr1a/b (Abcb1) or Mdr2 (Abcb4) gene disruption, the latter unable to secrete phospholipids and cholesterol into bile, were treated with griseofulvin to chemically induce protoporphyria. All groups showed dramatically increased PP levels in erythrocytes and liver after griseofulvin treatment. Histologically, massive PP deposits were found in livers of control and Mdr1a/b ؊/؊ mice but not in those of Mdr2 ؊/؊ mice. Serum unesterified cholesterol and phospholipids were increased by griseofulvin because of formation of lipoprotein-X in control and Mdr1a/b ؊/؊ mice only. Yet, bile flow was not impaired in griseofulvintreated mice, and biliary bile salt, phospholipid, and cholesterol secretion rates were significantly increased. Surprisingly, biliary PP excretion was similar in all 3 groups of griseofulvin-treated mice: the observed linear relationship between hepatic and biliary PP concentrations and identical liver-to-bile concentration ratios in treated and untreated mice suggest a passive mode of excretion. In conclusion, the data show that Mdr P-glycoproteins are not critically involved in biliary removal of excess PP and indicate that the presence of biliary lipids is required for formation of intrahepatic PP deposits. (HEPATOLOGY 2002;35: 299-306.) F errochelatase (EC 4.99.1.1) is a mitochondrial enzyme that transfers iron into protoporphyrin (PP) during the formation of heme. 1 In erythropoietic protoporphyria (EPP), an inherited disease caused by a mutated ferrochelatase gene, ferrochelatase activity is markedly reduced, i.e., in severe cases to 4% to 20% of control values. 2 Impaired ferrochelatase activity leads to a reduced heme synthesis rate and, via induction of the preceding steps in the biosynthetic cascade, to accumulation of the highly hydrophobic heme precursor PP in erythrocytes and liver. 1 Common clinical signs of EPP are erythema and edema caused by PP phototoxicity in the skin. 3 In the liver, PP deposits can be found both in cells and in small bile channels. 4 Severe hepatic complications in EPP are relatively rare, but indicative for transplantation in up to 10% of all cases. 5 PP is not enzymatically altered nor conjugated in the liver. 4 It is highly hydrophobic and is therefore removed from the body exclusively via the bile, followed by fecal excretion. 6 Mechanisms responsible for PP secretion into bile are currently not known. Previous studies performed by our laboratory showed association of PP with cholesterol/phospholipid vesicles in bile, 7 suggesting that these may act as PP carriers in this aqueous solution. Reduction of bilia...

show abstract

Isolation of two N-monosubstituted protoporphyrins, bearing either the whole drug or a methyl group on the pyrrole nitrogen atom, from liver of mice given griseofulvin

Cited by 24 publications

References 26 publications

A metabolomic perspective of griseofulvin-induced liver injury in mice

A metabolomic perspective of griseofulvin-induced liver injury in mice

Formation of N-methyl protoporphyrin in chemically-induced protoporphyria

Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria

Contact Info

Product

Resources

About