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Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism S

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Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism S Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2017/02/10/dmd.116.073254.DC1 1521-009X/45/4/375–389$25.00 http://dx.doi.org/10.1124/dmd.116.073254 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 45:375–389, April 2017 Copyright ª 2017 by The American Society for Pharmacology and Experimental Therapeutics Minireview Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism s Andrew J. Annalora, Craig B. Marcus, and Patrick L. Iversen Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon Received September 2, 2016; accepted February 6, 2017 Downloaded from ABSTRACT The human genome encodes 57 cytochrome P450 genes, whose to a disease pathology. The expansion of P450 transcript diversity enzyme products metabolize hundreds of drugs, thousands of xeno- involves tissue-specific splicing factors, transformation-sensitive al- biotics, and unknown numbers of endogenous compounds, including ternate splicing, trans-splicing between gene transcripts, single- steroids, retinoids, and eicosanoids. Indeed, P450 genes are the first nucleotide polymorphisms, and epigenetic regulation of alternate line of defense against daily environmental chemical challenges in a splicing. Homeostatic regulation of variant P450 expression is influ- dmd.aspetjournals.org manner that parallels the immune system. Several National Institutes of enced also by nuclear receptor signaling, suppression of nonsense- Health databases, including PubMed, AceView, and Ensembl, were mediated decay or premature termination codons, mitochondrial queried to establish a comprehensive analysis of the full human P450 dysfunction, or host infection. This review focuses on emergent transcriptome. This review describes a remarkable diversification of aspects of the adaptive gene-splicing process, which when viewed the 57 human P450 genes, which may be alternatively processed into through the lens of P450–nuclear receptor gene interactions, resem- nearly 1000 distinct mRNA transcripts to shape an individual’s P450 blesaprimitiveimmune-likesystemthat can rapidly monitor, respond, proteome. Important P450 splice variants from families 1A, 1B, 2C, 2D, and diversify to acclimate to fluctuations in endo-xenobiotic exposure. 3A, 4F, 19A, and 24A have now been documented, with some displaying Insights gained from this review should aid future drug discovery and at ASPET Journals on October 3, 2021 alternative subcellular distribution or catalytic function directly linked improve therapeutic management of personalized drug regimens. Introduction transcripts and polypeptide products will improve our ability to assess the Mapping the human genome sequence was completed in 2001 (Lander functional nature of its role in both physiologic and pathologic conditions et al., 2001), helping to usher in the “postgenomic era” of personalized (La Cognata et al., 2014). The spectrum of alternate splicing mechanisms medicine. Over a decade later, however, the promise of pharmacoge- underlying the expansion of the proteome involves the use of seven main nomics (PGx) has yet to fully materialize, and the composition of the splicing types, as previously described (Blencowe, 2006; Roy et al., human genome remains enigmatic, as numerous questions linger con- 2013). The molecular basis for these mechanisms is complex and beyond cerning the complexity of its content and organization. For example, how the scope of this review; however, a brief description of the phenomenon can a genome with only 22,000 genes produce a proteome with over and its key players is provided in the supplemental materials (see 200,000 distinct proteins? While transcription is a relatively well un- Supplemental Fig. 1). Here we will focus primarily on the spectrum of derstood phenomenon, the mechanisms involved in regulating alternative phenotypic outcomes induced by alternative transcript splicing, in precursor or unprocessed messenger RNA (pre-mRNA) splicing, the order to highlight the array of splice-sensitive features operating in the driving force behind both transcriptome and proteome expansion, remains cytochrome P450 (P450) superfamily, a collection of 57 human genes less appreciated. The ability to link a single gene to its full suite of RNA that coordinate the metabolism of both drugs and endoxenobiotics. This work focuses new attention on the biologic impact of alternative P450 gene splicing, an underappreciated component of phase I drug metabolism that may complicate or disrupt personalized approaches to This research was supported by start-up funds from the Office of Research and medicine. Precision medicine, therefore, through the universal applica- the College of Agricultural Sciences at Oregon State University (Corvallis, OR) awarded to Drs. Marcus and Iversen. tion of genetics, still faces many challenges beyond cost, ethical dx.doi.org/10.1124/dmd.116.073254. considerations, and the need for additional, whole genome sequences. s This article has supplemental material available at dmd.aspetjournals. Multiple resources have now been developed, in addition to the org. Human Genome Project, to address these challenges, including: the ABBREVIATIONS: BP, benzo(a)pyrene; ER, endoplasmic reticulum; GWAS, genome-wide association studies; NMD, nonsense-mediated decay; NR, nuclear receptor; P450, cytochrome P450; PGx, pharmacogenomics; PPAR, peroxisome proliferator–activated receptors; pre-mRNA, precursor or unprocessed messenger RNA; ROS, reactive oxygen species; SNP, single-nucleotide polymorphism; snRNA, small nuclear RNA; VDR, vitamin D receptor. 375 376 Annalora et al. Hapmap Project, which enables single-nucleotide polymorphism and intronic-splicing enhancers) with tissue-specific, trans-acting, (SNP) arrays for .100,000 SNPs; the 1000 Genomes Project; the splicing regulatory factors. In this way the same pre-mRNA transcript ENCODE project for noncoding RNAs; and the National Human can be processed into tissue-specific, alternately spliced forms (Wang Genome Research Institute (NHGRI) genome-wide association and Burge, 2008). The cytochrome P450 superfamily of genes is well studies (GWAS) catalog. GWAS have now identified two P450s studied from many perspectives (Guengerich, 2013; Johnson and that represent a biomarker for disease or a drug-response phenotype, Stout, 2013; Pikuleva and Waterman, 2013). As of late 2015, PubMed including: 1) a CYP2C8 association with bisphosphonate-related listed over 23,790 citations referencing human P450 genes (according osteonecrosis of the jaw in multiple myeloma (Sarasquete et al., to GeneCards.org), with much of this work being focused on tissue- 2008); and 2) a CYP2C19 association with clopidogrel interindividual specific expression or catalytic function of individual, reference forms. variation as an antiplatelet drug (Shuldiner et al., 2009). Aside from Alternative splicing of P450s has also been well studied for more than showing strong associations, few pharmacogenetic biomarkers of this two decades; however, the structural and functional diversity of P450 sort have successfully transitioned from discovery to clinical practice splice variants, and their relationship to human health and disease, (Carr et al., 2014). Many GWAS studies have failed to provide remains poorly understood. A summary of known P450 splice variants prognostic value because they are not designed to evaluate how linked to human disease is presented in Table 1. Reports from groups variant gene expression is influenced by both cellular and environ- attempting to synthesize a global view of alternative P450 splicing, mental splicing factors. In this regard, we feel a new appreciation is and its relevance to our understanding of human metabolism in the needed for the complexity of alternative splicing. For not only is the context of PGx or personalized medicine, are exceedingly rare world of both coding and noncoding RNA more diverse and more (Nelson et al., 2004; Turman et al., 2006). Downloaded from complex than we could have imagined even a decade ago, it is teeming Our review has led us to conclude that personalized approaches to with untold amounts of RNA “dark matter” and other relics of the medicine whose sole basis is GWAS may be misleading, in that they fail RNA world, whose structure and function must be fully appreciated to account for variability in compensatory splicing mechanisms, which and classified before a new guiding orthodoxy for “individualized can modulate the expression of some highly penetrant mutations. This medicine” can be safely conceived (St. Laurent et al., 2014; Cowie phenomenon is exemplified by ontogenetic regulatory factors that can et al., 2015). mask the physiologic impact of genetic variations among developmen- dmd.aspetjournals.org tally regulated P450 genes (Hines and McCarver, 2002). To expand on this concept, and explore the array of alternative splicing products that Meta-Analysis of Alternative Gene Splicing in the Cytochrome serve as an improved platform for predicting disease whose basis is the P450 Superfamily functional genome, we annotated all of the known human P450 splice Alternative splicing regulated by tissue-specific factors is a means of variants currently listed in the NCBI’s PubMed, AceView, and Ensembl adapting to physiologic demands. Tissue-specific splice variants may databases (Thierry-Mieg and Thierry-Mieg, 2006; Cunningham et al., arise from tissue-specific promoter elements
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