Cytochrome P450 3A4 (CYP3A4) metabolizes 30–50% of clinically used drugs. Large interperson variability in CYP3A4 activity affects response to CYP3A4 substrate drugs. We had demonstrated that an intronic single nucleotide polymorphism rs35599367 (CYP3A4*22, located in intron 6) reduces mRNA/protein expression; however, the underlying mechanism remained unknown. Here we show that CYP3A4*22 is associated with a two-fold or greater increase in formation of a nonfunctional CYP3A4 alternative splice variant with partial intron 6 retention in human liver (P=0.006), but not in small intestines. Consistent with this observation, in-vitro transfection experiments with a CYP3A4 minigene (spanning from intron 5 to intron 7) demonstrated that plasmids carrying the rs35599367 minor T allele caused significantly greater intron 6 retention than the C allele in liver derived HepG2 cells, but not in intestine-derived LS-174T cells. These results indicate that tissue-specific increased formation of nonfunctional alternative splice variant causes reduced CYP3A4 mRNA/protein expression in CYP3A4*22 carriers.
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Center for Pharmacogenomics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, Ohio, USA
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Correspondence to Danxin Wang, PhD, Center for Pharmacogenomics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, 333 West 10th Ave Graves Hall 5168, Columbus, OH 43210, USA Tel: +1 614 292 7336; fax: +1 614 292 7232; e-mail: firstname.lastname@example.org
Received January 26, 2015
Accepted September 28, 2015