Effects of heme arginate on cytochrome P450–mediated metabolism of drugs in patients with variegate porphyria and in healthy men

Mustajoki, Pertti; Mustajoki, Sami; Rautio, Arja; Arvela, P.; Pelkonen, Olavi

doi:10.1038/clpt.1994.94

Cited by 22 publications

(14 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, other hemoproteins, namely neuronal nitric oxide synthase and soluble guanylate cyclase, are reported to function normally in mice with limited heme (Jover et al, 2000). Our findings are in agreement with previous clinical studies in porphyria patients and healthy volunteers showing that the effect of heme in increasing drug metabolism is related to specific CYP isoforms (Mustajoki et al, 1994). Currently, we are investigating the isoform specificity of this effect using GFPfused CYP1A, CYP2C, and CYP3A isoforms.…”

Section: Discussionsupporting

confidence: 80%

Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency

Meyer

Lindberg²,

Hoffmann³

et al. 2005

Biological Chemistry

View full text Add to dashboard Cite

Previous work has demonstrated that the function of extrahepatic cytochrome P450 CYP1A1 is dependent on the availability of heme. CYP1A1 is involved in the activation of polyaromatic hydrocarbons. In the present study we used a transgenic mouse model with chronic impairment of heme synthesis -female porphobilinogen deaminase-deficient (PBGD -/-) mice -to investigate the effects of limited heme in untreated and b-naphthoflavone (b-NF)-treated animals on the function of CYP1A1 in brain. The heme content of PBGD -/-mice was diminished in the liver and brain compared to wild types. In the liver, partial heme deficiency led to less potent induction of CYP1A1 mRNA after b-NF treatment. In the brain, CYP1A1 protein was detected not only at the endoplasmic reticulum (ER), but also in the cytosol of PBGD -/-mice. Furthermore, 7-deethylation of ethoxyresorufin, an indicator of CYP1A1 metabolic activity, could be restored by heme in cytosol of PBGD -/-mouse brain. Independent of the genotype, we found only one cyp1a1 gene product, indicating that the cytosolic appearance of CYP1A1 most likely did not originate from mutant alleles. We conclude that heme deficiency in the brain leads to incomplete heme saturation of CYP1A1, which causes its improper incorporation into the ER membrane and persistence in the cytosol. It is suggested that diseases caused by relative heme deficiency, such as hepatic porphyrias, may lead to impaired hemoprotein function in brain.

show abstract

Section: Discussionsupporting

confidence: 80%

Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency

Meyer

Lindberg²,

Hoffmann³

et al. 2005

Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…However, CYP2B10, and other hemoproteins, namely neuronal nitric oxide synthase and soluble guanylate cyclase, are reported to function normally with limited heme [54]. This variability in heme response is in agreement with clinical studies in porphyria patients and healthy volunteers, whose P450 dependent drug metabolism is enhanced isoform specific after administration of exogenous heme [59,60].…”

Section: Availability Of Heme Is Essential For Brain P450 Functionsupporting

confidence: 63%

Expression and Function of Cytochrome P450 in Brain Drug Metabolism

Meyer¹,

Gehlhaus²,

Knoth³

et al. 2007

CDM

130

View full text Add to dashboard Cite

Cytochrome P450 (CYP, P450) is the collective term for a superfamily of heme-containing membrane proteins responsible for the metabolism of approximately 70 - 80 % of clinically used drugs. Besides the liver and other peripheral organs, P450 isoforms are expressed in glial cells and neurons of the brain. To enlighten their function and significance is a topic of high interest, as most of the neuroactive drugs used in therapy today are not only substrates, but also inducers of brain P450s with far reaching consequences. First of all, brain P450s are regulated differentially from those in liver. The availability of the prosthetic heme group appears to be essential for correct membrane insertion and enzymatic functionality of brain P450s. Furthermore, although not contributing to body's overall drug metabolism, brain P450s fulfil particular functions within specific cell types of the brain. In astrocytes of brain's border lines P450 isoforms are expressed at very high level. They form a metabolic barrier regulating drugs' influx, modulate blood-flow regulation, and act as signalling enzymes in inflammation. In neurons, however, P450s apparently have different function. In specified brain regions such as hypothalamus, hippocampus and striatum they provide signalling molecules like steroids and fatty acids necessary for neuronal outgrowth and maintenance. Induction of these P450s by neuroactive drugs can alter steroid hormone signalling directly in drug target cells, which may cause clinically relevant side effects like reproductive disorders and sexual or mental dysfunction. The understanding of brain P450 function appears to be of major interest in long-term drug mediated therapy of neurological diseases.

show abstract

“…b >90% protoporphyrin. c >70% coproporphyrin I. lism, replete deficient pools of haemoproteins and to enhance cytochrome P450 mediated metabolism [11,12]. However, haem therapy in EPP remains controversial.…”

Section: Discussionmentioning

confidence: 99%