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Catalytic Properties and Tissue Distribution of Cytochrome P450 4F8 and 4F12: Expression of CYP4F8 in Eye Tissues and Psoriatic Lesions
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human cytochrome P450 (CYP) family of monooxygenases is important for metabolism of drugs and endogenous compounds, e.g., vitamin A and D, cholesterol, steroids, fatty acids, and eicosanoids. This thesis describes the tissue distribution, catalytic properties, and possible function of CYP4F8 and CYP4F12. To this respect, methods for immunohistological analysis, and real-time PCR for analysis of their transcripts, were developed.

CYP4F8 was originally cloned from human seminal vesicles and proposed to catalyze 19-hydroxylation of prostaglandin H2 (PGH2). This notion could now be supported, as cyclooxygenase-2, CYP4F8, and microsomal prostaglandin E synthase-1 were found to be co-localized in the epithelial linings of seminal vesicles. The three enzymes were also co-localized in the suprabasal layers of epidermis, suggesting a similar function of CYP4F8 in skin. Real-time PCR showed that CYP4F8 mRNA was more than 10-fold increased in psoriatic lesions compared to non-lesional skin. CYP4F8 immunoreactivity was also found in kidney cortex, transitional epithelium, corneal epithelium, and retina. Although transcripts of all three enzymes were detectable in retina, no co-localization was found. Pro inflammatory stimuli were found to increase CYP4F8 mRNA expression in cultured epidermal and corneal keratinocytes. In these tissues CYP4F8 might oxidize fatty acids or other eicosanoids than PGH2.

CYP4F12 was originally cloned from the liver and small intestine, and found to oxidize arachidonic acid and two anti-histamines. Immunohistological studies showed that CYP4F12 immunoreactivity was present mainly in the gastrointestinal tract, e.g., stomach, ilium, and colon, but also in placenta. Although CYP4F8 and CYP4F12 have catalytic properties in common, there are important differences. CYP4F12 does not oxidize PGH2, certain eicosanoids, and fatty acids. The prominent expression in the gut suggests that CYP4F12 might be involved in oxidation of drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2005. , p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 8
Keyword [en]
Pharmaceutical pharmacology, Arachidonic acid metabolism, Cytochrome P450, 19-Hydroxyprostaglandins, Immunohistochemistry, Ocular tissues, Psoriasis
Keyword [sv]
Farmaceutisk farmakologi
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-5731ISBN: 91-554-6200-6 (print)OAI: oai:DiVA.org:uu-5731DiVA, id: diva2:166129
Public defence
2005-04-29, Room B22, Biomedicinskt Centrum (BMC), Husarg.3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2005-04-08 Created: 2005-04-08 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Expression of CYP4F8 (prostaglandin 19-hydroxylase) in human epithelia and prominent induction in epidermis of psoriatic lesions
Open this publication in new window or tab >>Expression of CYP4F8 (prostaglandin 19-hydroxylase) in human epithelia and prominent induction in epidermis of psoriatic lesions
2003 In: Arch Biochem Biophys, Vol. 409, no 1, p. 188-96Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92820 (URN)
Available from: 2005-04-08 Created: 2005-04-08Bibliographically approved
2. Expression of Cyclooxygenase-2, Cytochrome P450 4F8, and Microsomal Prostaglandin E Synthase-1 in Psoriatic Lesions and Epidermal Keratinocytes
Open this publication in new window or tab >>Expression of Cyclooxygenase-2, Cytochrome P450 4F8, and Microsomal Prostaglandin E Synthase-1 in Psoriatic Lesions and Epidermal Keratinocytes
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92821 (URN)
Available from: 2005-04-08 Created: 2005-04-08Bibliographically approved
3. CYP4F8 in Plexiform Layers of the Retina and CYP4F8 Expression in Human Corneal Epithelium
Open this publication in new window or tab >>CYP4F8 in Plexiform Layers of the Retina and CYP4F8 Expression in Human Corneal Epithelium
Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-92822 (URN)
Available from: 2005-04-08 Created: 2005-04-08Bibliographically approved
4. On the mechanism of biosynthesis of 19-hydroxyprostaglandins of human seminal fluid and expresssion of cyclooxygenase-2, PGH 19-hydroxylas (CYP4F8) and microsomal PGE synthase-1 in seminal vesicles and vas deferens
Open this publication in new window or tab >>On the mechanism of biosynthesis of 19-hydroxyprostaglandins of human seminal fluid and expresssion of cyclooxygenase-2, PGH 19-hydroxylas (CYP4F8) and microsomal PGE synthase-1 in seminal vesicles and vas deferens
Show others...
2005 (English)In: Prostaglandins & other lipid mediators, ISSN 1098-8823, E-ISSN 2212-196X, Vol. 75, no 1-4, p. 47-64Article in journal (Refereed) Published
Abstract [en]

The predominating prostaglandins of human seminal fluid are 19R-hydroxyprostaglandins E1 and E2, conceivably formed sequentially by prostaglandin H (PGH) synthase-2, PGH 19-hydroxylase (CYP4F8), and microsomal PGE synthase-1 of seminal vesicles. Our aim was to study this enzyme system. Quantification by real-time PCR suggested that the transcripts of PGH synthase-2, CYP4F8, and microsomal PGE synthase-1 were abundant and correlated in seminal vesicles of seven patients (p < 0.05). The three enzymes were detected in seminal vesicles by Western blot analysis, and immunohistological analysis confirmed the localization to the epithelia of seminal vesicles and distal vas deferens. Immunofluorescence analysis showed co-localization of the three enzymes in epithelial cells of seminal vesicles and vas deferens. 19-Hydroxy-PGE compounds were detected by mass spectrometry in the mucosa of distal vas deferens. Recombinant CYP4F8 catalyzes n-2 hydroxylation of PGH1 and PGH2 and n-3 hydroxylation of arachidonic acid. Arachidonic acid was oxidized to 18-hydroxyarachidonic acid and to PGE2 and by microsomes of seminal vesicles in the presence of NADPH and GSH, and to relatively small amounts of 19-hydroxy-PGE2. We conclude that PGH synthase-2, CYP4F8, and PGE synthase-1 likely forms 19-hydroxy-PGE compounds in seminal vesicles and vas deferens, but the catalytic properties of CYP4F8 suggest additional biological functions. Recombinant CYP4F8 was also found to catalyze n-2 hydroxylation of PGI2 and carbaprostacyclin (Km to approximately 40 microM), and n-2 and n-3 hydroxylation of carbocyclic TXA2.

Keyword
Carbaprostacyclin, Co-localization, Hydroxyprostaglandin, Immunohistochemistry, Real-time PCR, Liquid chromatography-mass spectrometry
National Category
Pharmaceutical Sciences Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92823 (URN)10.1016/j.prostaglandins.2004.09.014 (DOI)15789615 (PubMedID)
Available from: 2005-04-08 Created: 2005-04-08 Last updated: 2018-01-13Bibliographically approved
5. Oxidation of Prostaglandin (H2) and prostaglandin H(2) analogues by human cytochromes P450: analysis of omega-side chain hydroxy metabolites and four stereoisomers of 5-hydroxy-prostaglandin I(1) by mass spectrometry
Open this publication in new window or tab >>Oxidation of Prostaglandin (H2) and prostaglandin H(2) analogues by human cytochromes P450: analysis of omega-side chain hydroxy metabolites and four stereoisomers of 5-hydroxy-prostaglandin I(1) by mass spectrometry
2001 In: Biochem Pharmacol, Vol. 62, p. 407-15Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92824 (URN)
Available from: 2005-04-08 Created: 2005-04-08Bibliographically approved
6. CYP4F12 expresssion in gastrointestinal and urogenital epithelia
Open this publication in new window or tab >>CYP4F12 expresssion in gastrointestinal and urogenital epithelia
2004 In: Basic Clin Pharmacol Toxicol, Vol. 94, p. 177-83Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92825 (URN)
Available from: 2005-04-08 Created: 2005-04-08Bibliographically approved
7. Oxygenation of Polyunsaturated Long Chain Fatty Acids by Recombinant CYP4F8 and CYP4F12: Catalytic Importance of Gly-328 and Tyr-125 of CYP4F8 in Oxygenation fo Arachidonic acid and PGH2 Analogs
Open this publication in new window or tab >>Oxygenation of Polyunsaturated Long Chain Fatty Acids by Recombinant CYP4F8 and CYP4F12: Catalytic Importance of Gly-328 and Tyr-125 of CYP4F8 in Oxygenation fo Arachidonic acid and PGH2 Analogs
Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92826 (URN)
Available from: 2005-04-08 Created: 2005-04-08 Last updated: 2010-01-13Bibliographically approved

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