Alteration of mRNA levels of δ-aminolevulinic acid synthase, ferrochelatase and heme oxygenase-1 in griseofulvin induced protoporphyria mice

Inafuku, K.; Takamiyagi, Atsushi; Oshiro, Minoru; Kinjo, Takashi; Nakashima, Yoshiki; Nonaka, Shigeo

doi:10.1016/s0923-1811(98)00073-5

Cited by 14 publications

(17 citation statements)

References 32 publications

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“…Table 2. type CYP2B10, was highly elevated (Figure 7) in line with gene array analysis in our previous study. 17 As in other studies 38 and the Fech mouse (Table 2) no marked compensatory increase in ferrochelase RNA was detected (data not shown).…”

Section: Comparison Of Fech and Griseofulvin Porphyric Micesupporting

confidence: 79%

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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Section: Comparison Of Fech and Griseofulvin Porphyric Micesupporting

confidence: 79%

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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“…cDNAs were synthesized from 5 g (2 l) of total RNA by using Moloney murine leukemia virus reverse transcriptase (Toyobo, Osaka, Japan) and oligo(dT) [12][13][14][15][16][17][18] primers (Gibco-BRL Products, Gaithersburg, Md.). Two microliters (5 g) of total RNA was reverse transcribed by specific priming to first-strand cDNA as described by Inafuku et al (19). PCR amplification was performed with a PT-100 programmable thermal cycler (MJ Research, Inc., Watertown, Mass.).…”

Section: Methodsmentioning

confidence: 99%

Low-Dose UVB Contributes to Host Resistance againstLeishmania amazonensisInfection in Mice through Induction of Gamma Interferon and Tumor Necrosis Factor Alpha Cytokines

Khaskhely

Maruno

Uezato

et al. 2002

Clin Vaccine Immunol

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UV radiation suppresses the immune response, a fact which raises the question of whether the phenomenon may find practical applications in the outcome of infectious diseases. In this study, BALB/c mice were exposed to low-dose UVB (250 J/m 2 ) from Dermaray M-DMR-100 for 4 consecutive days. Twelve hours after the last UV exposure, groups of mice were injected with 2 ؋ 10 6 Leishmania amazonensis promastigotes. The development of skin lesions, as assessed by measurement of visible cutaneous lesions, was significantly suppressed in low-dose UVB-irradiated mice compared to nonirradiated controls. In order to characterize the cytokines involved in this phenomenon, BALB/c mice were irradiated with identical doses of UVB, and gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), and interleukin 4 cytokine levels in blood serum and skin were examined at different times by a sandwich enzyme-linked immunosorbent assay, immunohistochemical analysis, and reverse transcription (RT)-PCR. Upregulated expression of serum IFN-␥ and TNF-␣ was observed from 6 to 24 h. Positive results for IFN-␥ and TNF-␣ in UVB-irradiated mice were obtained by immunohistochemical analysis. By RT-PCR, the mRNA expression of both IFN-␥ and TNF-␣ cytokines was detected in a time-dependent manner only in UVB-irradiated mice. Histopathological analysis and electron microscopy revealed that cellular infiltration, tissue parasitism, and parasitophorus vacuoles in irradiated mice were markedly less noticeable than those in nonirradiated controls. These results suggested that low-dose UVB irradiation played a pathogen-suppressing role in Leishmania-susceptible BALB/c mice via systemic and local upregulation of Th1 (IFN-␥ and TNF-␣) cytokines.

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“…After longterm ingestion of GF, the mice showed hepatomegaly, degenerative rearrangement, deposition of porphyrins, -ings of previous reports (Inafuku et al, 1999;Berenson et al, 1991;Choi et al, 1991). Chronic hepatic injury may cause neuropsychiatric symptoms such as aggressiveness and loss of consciousness, as observed in hepatic encephalopathy (Ostapowicz et al, 2002).…”

Section: Discussionmentioning

confidence: 58%

“…Protoporphyria model mice have a mutated ferrochelatase (FC) gene that encodes a mitochondrial enzyme to catalyze the insertion of a ferrous ion into PPIX at the last step of heme biosynthesis; these mice exhibit hemolytic anemia, splenic enlargement, and cholestasis, but the heme regulatory pool in the liver is still maintained (Davies et al, 2005). Long-term administration of griseofulvin (GF) to rodent produces a well-established animal model for hepatic porphyria (De Matteis and Rimington, 1963;Hawkins et al, 1986;Berenson et al, 1991;Inafuku et al, 1999). GF is metabolized by cytochrome P450 with the concomitant production of NMPP, an inhibitor of FC; NMPP subsequently prevents heme biosynthesis and allows for the accumulation of heme precursors, especially the immediately preceding precursor, PPIX.…”

Section: Introductionmentioning

confidence: 99%

“…GF is metabolized by cytochrome P450 with the concomitant production of NMPP, an inhibitor of FC; NMPP subsequently prevents heme biosynthesis and allows for the accumulation of heme precursors, especially the immediately preceding precursor, PPIX. Mice with GF-induced porphyria exhibit disturbances in heme metabolism (De Matteis and Rimington, 1963), liver injury (Inafuku et al, 1999;Berenson et al, 1991;Choi et al, 1991), andet al, 1986); however, little is known about the neuropsychiatric symptoms in these mice. In the present study, we evaluated psychiatric behaviors such as mouse-model anxiety and depression, as well as other pathological states, in association with disturbances in heme metabolism following GF ingestion.…”

Section: Introductionmentioning

confidence: 99%

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Manifestation of psychiatric behaviors in a mouse model of griseofulvin-induced hepatic porphyria

et al. 2008

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-Most patients with hepatic porphyria exhibit neuropsychiatric symptoms, including abdominal pain, peripheral neuropathy, confusion, insomnia and mental disturbances such as anxiety and for neuropsychiatric manifestations in patients with acute porphyria, the pathogenetic mechanisms remain poorly understood. In the present study, we observed psychiatric behaviors in mice with hepatic porphyria induced by the ingestion of a griseofulvin (GF)-containing diet over a period of 12 weeks. GF ingestion by the mice caused an accumulation of porphyrins in the feces and a decrease in heme in the liver; these effects were observed throughout the entire duration of the experiment, with maximum levels observed after circa 1 week of ingestion of this diet. In addition, the mice developed enlargement of the liver, hepatocyte injury, and cholestasis. Mice with hepatic porphyria manifested an anxiety-like behavior by the long-term treatment (over 5 weeks) in a GF-dose and duration dependent manner. The hepatic porphyria mice also manifested depression-like behaviors by the short-term treatment (3 weeks) of GF2.0, which demonstrated psychiatric manifestations in GF-induced hepatic porphyria mice. The present results suggest that model animals could be useful for elucidating the mechanisms underlying psychiatric manifestations in syndromes such as hepatic porphyria and hepatic encephalopathy that are associated with the impairment of hepatic function.

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Alteration of mRNA levels of δ-aminolevulinic acid synthase, ferrochelatase and heme oxygenase-1 in griseofulvin induced protoporphyria mice

Cited by 14 publications

References 32 publications

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

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

Low-Dose UVB Contributes to Host Resistance againstLeishmania amazonensisInfection in Mice through Induction of Gamma Interferon and Tumor Necrosis Factor Alpha Cytokines

Manifestation of psychiatric behaviors in a mouse model of griseofulvin-induced hepatic porphyria

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