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Drug Metabolism and Disposition Fast Forward
First published on October 6, 2008; DOI: 10.1124/dmd.108.023663

0090-9556/09/3701-1-4$20.00
DMD 37:1-4, 2009

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SHORT COMMUNICATION

Expression and Functional Analysis of CYP2D6.24, CYP2D6.26, CYP2D6.27, and CYP2D7 IsozymesFormula

Wei-Yan Zhang, You-Bin Tu, Robert L. Haining, and Ai-Ming Yu

Department of Basic Pharmaceutical Sciences, School of Pharmacy, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia (W.-Y.Z., Y.-B.T., R.L.H.); and Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, SUNY, Buffalo, New York (W.-Y.Z., A.-M.Y.)

The objectives of this study were to compare the drug-metabolizing activity of human CYP2D6.24 (I297L), CYP2D6.26 (I369T), and CYP2D6.27 (E410K) allelic isoforms with wild-type CYP2D6.1 and to express the CYP2D7 protein derived from an indel polymorphism (CYP2D7 138delT) and investigate its possible codeine O-demethylase activity. Successful creation of individual cDNAs corresponding to CYP2D6*24 (2853 A>C), CYP2D6*26 (3277 T>C), and CYP2D6*27 (3853 G>A) allelic variants and CYP2D7 was achieved via molecular cloning. The corresponding proteins, CYP2D6.24, CYP2D6.26, CYP2D6.27, and CYP2D7, were expressed in insect cells by using a baculovirus-mediated expression system. All CYP2D proteins showed the empirical carbon monoxide difference spectra. We were surprised to find that the CYP2D7 protein was detected mainly in mitochondrial fractions, whereas all CYP2D6 allelic isoforms were present in the microsomal fraction. Furthermore, CYP2D7 did not produce any morphine from codeine. In contrast, CYP2D6.24, CYP2D6.26, and CYP2D6.27 allelic isoforms all showed active drug-metabolizing activities toward both codeine and dextromethorphan O-demethylation. Whereas CYP2D6.24 exhibited the highest intrinsic clearance in dextromethorphan O-demethylation (~6-fold higher than that by CYP2D6.1), it had the lowest enzyme efficiency in codeine O-demethylation (~50% lower than that by CYP2D6.1). Overall, the enzymatic consequences of CYP2D6 allelic isozymes are substrate dependent. These data would help preclinical and clinical assessments of the metabolic elimination of drugs that are mediated by human CYP2D enzyme.

Address correspondence to: Dr. Robert L. Haining, Department of Basic Pharmaceutical Sciences, School of Pharmacy, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, West Virginia 26506. E-mail: rob{at}mirrorsimage.com




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[Abstract] [Full Text] [PDF]


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