Novel extrahepatic P450 enzymes with emphasis on the tumor specific CYP2W1
Author: Karlgren, Maria
Date: 2007-04-26
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet
Time: 09.00
Department: Institutionen för fysiologi och farmakologi / Department of Physiology and Pharmacology
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thesis.pdf (395.1Kb)
Abstract
Cytochrome P450 is a superfamily of enzymes involved in the metabolism of
endogenous and exogenous compounds. The P450 enzymes are expressed at
high levels in the liver, but are also found in extrahepatic tissues and
in transformed tissues. The expression of P450s in tumors has drawn
interest because their presence might influence cancer therapy and since
the enzymes may be utilized as drug targets in new cancer therapy
strategies. In the current study two novel extrahepatic P450s, CYP2U1 and
CYP2W1, were identified and characterized. The expression of CYP2W1 in
transformed tissues was investigated, resulting in the proposal for
CYP2W1 as a novel potential drug target for colon cancer therapy.
CYP2U1 was cloned and identified as a highly conserved P450, having an
ortholog in Fugu fish (Takifugu rubripes). The gene contained only 5
exons and the deduced amino acid sequence harbored two unique
NH2-terminal stretches, with one of them being proposed to be important
for efficient folding. The CYP2U1 cDNA was expressed in HEK293 cells
yielding a properly folded enzyme. Antibodies were developed against a
human COOH-terminal sequence, and analysis showed that the CYP2U1 mRNA
and/or protein from human and rat were found to be expressed especially
in brain, in particular in the limbic structures and cortex, and in
thymus. It is suggested that the enzyme can be used as a target for drugs
in brain.
CYP2W1, initially found as a partial clone in HepG2 cells, was cloned and
expressed in HEK293 cells yielding an enzyme with a proper folding
capable of metabolizing arachidonic acid. Antibodies were developed and
showed the presence of three different immunoreactive bands in Western
blotting, probably representing different post-translational
modifications. In adult human tissues, CYP2W1 mRNA was found to be
expressed at no or very low levels. In rat, high mRNA expression was seen
in fetal colon, with expression levels increasing by fetal age and then
decreasing again after birth, but CYP2W1 was not seen in other adult
tissues investigated. CYP2W1 mRNA was expressed in human tumors
originating from the adrenals and colon. High CYP2W1 mRNA and protein
expression were especially seen in Caco-2TC7 cells and colon tumors. The
CYP2W1 gene was found to contain CpG islands, and demethylation of a CpG
island located in the exon1-intron 1 region appeared to be required for
expression in tumor samples. It is concluded that CYP2W1 most probably is
a colonic enzyme expressed in fetal life and overexpressed in about 50%
of human colon tumors, which suggest the use of the enzyme as drug target
in cancer therapy. However, more studies are needed in order to fully
understand its role in tumor biology and its potential as drug target.
List of papers:
I. Karlgren M, Backlund M, Johansson I, Oscarson M, Ingelman-Sundberg M (2004). "Characterization and tissue distribution of a novel human cytochrome P450-CYP2U1." Biochem Biophys Res Commun 315(3): 679-85
Pubmed
II. Karlgren M, Miura S, Ingelman-Sundberg M (2005). "Novel extrahepatic cytochrome P450s." Toxicol Appl Pharmacol 207(2 Suppl): 57-61
Pubmed
III. Karlgren M, Gomez A, Stark K, Svard J, Rodriguez-Antona C, Oliw E, Bernal ML, Ramon y Cajal S, Johansson I, Ingelman-Sundberg M (2006). "Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1." Biochem Biophys Res Commun 341(2): 451-8. Epub 2006 Jan 11
Pubmed
IV. Karlgren M, Ingelman-Sundberg M (2007). "Tumour-specific expression of CYP2W1: its potential as a drug target in cancer therapy." Expert Opin Ther Targets 11(1): 61-7
Pubmed
V. Gomez A, Karlgren M, Edler D, Bernal ML, Mkrtchian S, Ingelman-Sundberg M (2007). "Expression of cytochrome P450 2W1 (CYP2W1) in colon tumors; regulation by gene methylation." (Manuscript)
I. Karlgren M, Backlund M, Johansson I, Oscarson M, Ingelman-Sundberg M (2004). "Characterization and tissue distribution of a novel human cytochrome P450-CYP2U1." Biochem Biophys Res Commun 315(3): 679-85
Pubmed
II. Karlgren M, Miura S, Ingelman-Sundberg M (2005). "Novel extrahepatic cytochrome P450s." Toxicol Appl Pharmacol 207(2 Suppl): 57-61
Pubmed
III. Karlgren M, Gomez A, Stark K, Svard J, Rodriguez-Antona C, Oliw E, Bernal ML, Ramon y Cajal S, Johansson I, Ingelman-Sundberg M (2006). "Tumor-specific expression of the novel cytochrome P450 enzyme, CYP2W1." Biochem Biophys Res Commun 341(2): 451-8. Epub 2006 Jan 11
Pubmed
IV. Karlgren M, Ingelman-Sundberg M (2007). "Tumour-specific expression of CYP2W1: its potential as a drug target in cancer therapy." Expert Opin Ther Targets 11(1): 61-7
Pubmed
V. Gomez A, Karlgren M, Edler D, Bernal ML, Mkrtchian S, Ingelman-Sundberg M (2007). "Expression of cytochrome P450 2W1 (CYP2W1) in colon tumors; regulation by gene methylation." (Manuscript)
Issue date: 2007-04-05
Rights:
Publication year: 2007
ISBN: 978-91-7357-139-5
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