HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 26, 27383-27389, June 25, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/26/27383    most recent M402337200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pai, H. V. Articles by Ravindranath, V. Search for Related Content PubMed PubMed Citation Articles by Pai, H. V. Articles by Ravindranath, V. Social Bookmarking                      What's this?

A Frameshift Mutation and Alternate Splicing in Human Brain Generate a Functional Form of the Pseudogene Cytochrome P4502D7 That Demethylates Codeine to Morphine^*

Harish V. Pai, Reddy P. Kommaddi, Shankar J. Chinta, Toshiyuki Mori, Michael R. Boyd¶, and Vijayalakshmi Ravindranath||

From the National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India, the Molecular Targets Development Program, Center for Cancer Research, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702-1201, and the ^¶Cancer Research Institute, University of South Alabama, Mobile, Alabama 36688-0002

A frameshift mutation 138delT generates an open reading frame in the pseudogene, cytochrome P4502D7 (CYP2D7), and an alternate spliced functional transcript of CYP2D7 containing partial inclusion of intron 6 was identified in human brain but not in liver or kidney from the same individual. mRNA and protein of the brain variant CYP2D7 were detected in 6 of 12 human autopsy brains. Genotyping revealed the presence of the frameshift mutation 138delT only in those human subjects who expressed the brain variant CYP2D7. Genomic DNA analysis in normal volunteers revealed the presence of functional CYP2D7 in 4 of 8 individuals. In liver, the major organ involved in drug metabolism, a minor metabolic pathway mediated by CYP2D6 metabolizes codeine (pro-drug) to morphine (active drug), whereas norcodeine is the major metabolite. In contrast, when expressed in Neuro2a cells, brain variant CYP2D7 metabolized codeine to morphine with greater efficiency compared with the corresponding activity in cells expressing CYP2D6. Morphine binds to µ-opioid receptors in certain regions of the central nervous system, such as periaqueductal gray, and produces pain relief. The brain variant CYP2D7 and µ-opioid receptor colocalize in neurons of the periaqueductal gray area in human brain, indicating that metabolism of codeine to morphine could occur at the site of opioid action. Histio-specific isoforms of P450 generated by alternate splicing, which mediate selective metabolism of pro-drugs within tissues, particularly the brain, to generate active drugs may play an important role in drug action and provide newer insights into the genetics of metabolism.

Received for publication, March 2, 2004 , and in revised form, March 23, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY220845.

^* This work was supported by National Institutes of Health Grant MH55494. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Molecular and Cellular Neuroscience, National Brain Research Centre, Nainwal Mode, Manesar, Haryana 122050, India. E-mail: vijir{at}nbrc.ac.in.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				W.-Y. Zhang, Y.-B. Tu, R. L. Haining, and A.-M. Yu Expression and Functional Analysis of CYP2D6.24, CYP2D6.26, CYP2D6.27, and CYP2D7 Isozymes Drug Metab. Dispos., January 1, 2009; 37(1): 1 - 4. [Abstract] [Full Text] [PDF]

				A. Bhathena, T. Mueller, D. R. Grimm, K. Idler, A. Tsurutani, B. B. Spear, and D. A. Katz Frequency of the Frame-Shifting CYP2D7 138delT Polymorphism in a Large, Ethnically Diverse Sample Population Drug Metab. Dispos., August 1, 2007; 35(8): 1251 - 1253. [Abstract] [Full Text] [PDF]

				A. Yao, R. Charlab, and P. Li Systematic identification of pseudogenes through whole genome expression evidence profiling Nucleic Acids Res., September 11, 2006; 34(16): 4477 - 4485. [Abstract] [Full Text] [PDF]

				A. Gaedigk and J. S. Leeder COMMENTS ON HOSKINS ET AL. [(2005) DRUG METAB DISPOS 33:1564-1565] Drug Metab. Dispos., March 1, 2006; 34(3): 504 - 505. [Full Text] [PDF]

				H. V. Pai and V. Ravindranath RESPONSE TO COMMENTS ON HOSKINS ET AL. [(2005) DRUG METAB DISPOS 33:1564-1565] Drug Metab. Dispos., March 1, 2006; 34(3): 506 - 506. [Full Text] [PDF]

				W. Zhu, P. Cadet, G. Baggerman, K. J. Mantione, and G. B. Stefano Human White Blood Cells Synthesize Morphine: CYP2D6 Modulation J. Immunol., December 1, 2005; 175(11): 7357 - 7362. [Abstract] [Full Text] [PDF]

				J. M. Hoskins, S. Marsh, and H. L. McLeod COMMENT ON "A FRAMESHIFT MUTATION AND ALTERNATE SPLICING IN HUMAN BRAIN GENERATE A FUNCTIONAL FORM OF THE PSEUDOGENE CYTOCHROME P4502D7 THAT DEMETHYLATES CODEINE TO MORPHINE" Drug Metab. Dispos., October 1, 2005; 33(10): 1564 - 1565. [Full Text] [PDF]

				H. V. Pai and V. Ravindranath RESPONSE TO COMMENT ON "A FRAMESHIFT MUTATION AND ALTERNATE SPLICING IN HUMAN BRAIN GENERATE A FUNCTIONAL FORM OF THE PSEUDOGENE CYTOCHROME P4502D7 THAT DEMETHYLATES CODEINE TO MORPHINE" Drug Metab. Dispos., October 1, 2005; 33(10): 1566 - 1566. [Full Text] [PDF]

				Y. Caraco Genes and the Response to Drugs N. Engl. J. Med., December 30, 2004; 351(27): 2867 - 2869. [Full Text] [PDF]