CYP1A1 and CYP1B1 in Blood-Brain Interfaces: CYP1A1-Dependent Bioactivation of 7,12-Dimethylbenz(a)anthracene in Endothelial Cells

Granberg, Lizette; Östergren, Anna; Brandt, Ingvar; Brittebo, Eva B.

doi:10.1124/dmd.31.3.259

Cited by 55 publications

(45 citation statements)

References 37 publications

(36 reference statements)

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“…CYP1A2 is unlikely to be the source of the massively elevated MEL metabolite levels in the cerebral cortex. On the other hand, various elements of the mouse blood-brain barrier, including the cerebral arteries and arterioles, have been reported to have very high levels of CYP1B1 that apparently were not further inducible (Granberg et al, 2003). It is possible that CYP1B1 played a role in the sequestration of high concentrations of 6-HMEL sulfate in mouse cerebral cortex.…”

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

confidence: 99%

“…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%

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Metabolism of Melatonin by Human Cytochromes P450

Ma¹,

Idle²,

Krausz³

et al. 2004

Drug Metab Dispos

288

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

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Metabolism of Melatonin by Human Cytochromes P450

Ma¹,

Idle²,

Krausz³

et al. 2004

Drug Metab Dispos

288

231

View full text Add to dashboard Cite

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“…Controls were incubated at 0°C. The samples were transferred to ice-cold 4% phosphate-buffered formaldehyde, pH 7, immediately after incubation and processed as described by Granberg et al (2003). The formalinfixed endometrial biopsy samples incubated with […”

Section: Methodsmentioning

confidence: 99%

“…The maintenance of the normal cellular architecture and enzyme activity makes tissue explants attractive for studies using light microscopic autoradiographic techniques to visualize cell-specific bioactivation of radiolabeled chemicals (Brittebo and Brandt, 1997). By using this approach, we have previously identified unforeseen sites of local bioactivation of chemicals in rodent extrahepatic tissues, and some potent and cell-specific toxicants have been shown (Annas and Brittebo, 1998;Granberg et al, 2003).…”

mentioning

confidence: 99%

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

Andersson

Helmestam²,

Żebrowska³

et al. 2009

Drug Metab Dispos

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“…In addition to MRPs, several drug-metabolizing enzymes have been shown to be expressed in the barrier including epoxide hydrolase, glutathione S-transferase, and various isoforms of the cytochrome P450 and UDPglucuronosyltransferase families (Ghersi-Egea et al, 1994;Lawrenson et al, 1999;Miksys and Tyndale, 2002;Granberg et al, 2003). Biotransformation of foreign compounds via these phase I and II enzymes might result in metabolites that can then be removed from the brain by efflux transporters such as MRPs.…”

mentioning

confidence: 99%