Constitutive and inducible levels of CYP1A1 and CYP1A2 in rat cerebral cortex and cerebellum

Iba, Michael M.; Storch, Amijoy; Ghosal, Anima; Bennett, Susan E.; Reuhl, Kenneth R.; Lowndes, Herbert E.

doi:10.1007/s00204-003-0488-1

Cited by 32 publications

(18 citation statements)

References 47 publications

(59 reference statements)

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“…This large increase in luciferase activity may in part be a result of basal luciferase activity that is nearly 100-fold higher than that observed in livers from untreated mice. Elevated levels of constitutive luciferase activity are in agreement with reports that Cyp1a1 is constitutively expressed in rodent brain (39,40). These results are also in agreement with previously published observations indicating that induced levels of Cyp1a1 accumulate in rat cerebral cortex and cerebellum (39).…”

Section: Characterization Of Hepatic Cyp1a1-luciferase Expression In supporting

confidence: 93%

“…Mouse Cyp1a1 is expressed constitutively and induced in adult brain (39,40), and we demonstrated that TCDD was capable of inducing CYP1A1-luciferase activity in adult brain from CYPLucR mice. In contrast, induction of CYP1A1-luciferase in brains from neonatal mice that were receiving TCDD through lactational exposure showed minimal induction.…”

Section: Discussionmentioning

confidence: 75%

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The Human CYP1A1 Gene Is Regulated in a Developmental and Tissue-specific Fashion in Transgenic Mice

Galijatovic

Beaton

Nguyen

et al. 2004

Journal of Biological Chemistry

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Section: Characterization Of Hepatic Cyp1a1-luciferase Expression In supporting

confidence: 93%

Section: Discussionmentioning

confidence: 75%

The Human CYP1A1 Gene Is Regulated in a Developmental and Tissue-specific Fashion in Transgenic Mice

Galijatovic

Beaton

Nguyen

et al. 2004

Journal of Biological Chemistry

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“…CYP1A1 is expressed predominantly in extrahepatic tissue and abundantly in brain (McFayden et al, 1998;Iba et al, 2003). Our previous in vitro studies have suggested that heme deficiency leads to increased accumulation of CYP1A1 in the cytosol of COS-1 cells and untreated male mice .…”

Section: Discussionmentioning

confidence: 99%

Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency

Meyer

Lindberg²,

Hoffmann³

et al. 2005

Biological Chemistry

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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.

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“…However, heart and cerebral cortex displayed 30-to 50-and 60-to 1400-fold excesses of 6-HMEL, respectively. Uninduced rat cerebral cortex contains relatively little CYP1A2, but this can be induced considerably by ␤-naphthoflavone treatment (Iba et al, 2003). CYP1A2 is unlikely to be the source of the massively elevated MEL metabolite levels in the cerebral cortex.…”

Section: Michaelis-menten Parameters Estimated For Melatonin 6-hydroxmentioning

confidence: 96%

“…CYP1B1-mediated MEL 6-hydroxylation was then investigated in an organ that expresses CYP1B1, together with other CYP1 forms. Mouse brain was used because this organ was reported to express all three CYP1 forms (Granberg et al, 2003;Iba et al, 2003). In addition, whole brain homogenates were used for these studies in light of a report that CYP1B1 may be expressed in the nuclei of brain and other tissues (Muskhelishvili et al, 2001).…”

Section: Downloaded Frommentioning

confidence: 99%

Metabolism of Melatonin by Human Cytochromes P450

Ma¹,

Idle²,

Krausz³

et al. 2004

Drug Metab Dispos

282

231

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ABSTRACT:In humans, the pineal hormone melatonin (MEL) is principally metabolized to 6-hydroxymelatonin (6-HMEL), which is further conjugated with sulfate and excreted in urine. MEL O-demethylation represents a minor reaction. The exact role of individual human cytochromes P450 (P450s) in these pathways has not been established. We used a panel of 11 recombinant human P450 isozymes to investigate for the first time the 6-hydroxylation and O-demethylation of MEL. CYP1A1, CYP1A2, and CYP1B1 all 6-hydroxylated MEL, with CYP2C19 playing a minor role. These reactions were NADPH-dependent. CYP2C19 and, to some extent CYP1A2, Odemethylated MEL. The K m (M) and V max (k cat , pmol min ؊1 pmol ؊1 P450) for 6-hydroxylation were estimated as 19.2 ؎ 2.01 and 6.46 ؎ 0.22 (CYP1A1), 25.9 ؎ 2.47 and 10.6 ؎ 0.32 (CYP1A2), and 30.9 ؎ 3.76 and 5.31 ؎ 0.21 (CYP1B1). These findings confirm the suggestion of others that CYP1A2 is probably the foremost hepatic P450 in the 6-hydroxylation of MEL and a single report that CYP1A1 is also able to mediate this reaction. However, this is the first time that CYP1B1 has been shown to 6-hydroxylate MEL. The IC 50 for the CYP1B1-selective inhibitor (E)-2,4,3,5-tetramethoxystilbene was estimated to be 30 nM for MEL 6-hydroxylation by recombinant human CYP1B1. Comparison of brain homogenates from wild-type and cyp1b1-null mice revealed that MEL 6-hydroxylation was clearly mediated to a significant degree by CYP1B1. CYP1B1 is not expressed in the liver but has a ubiquitous extrahepatic distribution, and is found at high levels in tissues that also accumulate either MEL or 6-HMEL, such as intestine and cerebral cortex, where it may assist in regulating levels of MEL and 6-HMEL.

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Constitutive and inducible levels of CYP1A1 and CYP1A2 in rat cerebral cortex and cerebellum

Cited by 32 publications

References 47 publications

The Human CYP1A1 Gene Is Regulated in a Developmental and Tissue-specific Fashion in Transgenic Mice

The Human CYP1A1 Gene Is Regulated in a Developmental and Tissue-specific Fashion in Transgenic Mice

Cytosolic persistence of mouse brain CYP1A1 in chronic heme deficiency

Metabolism of Melatonin by Human Cytochromes P450

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