Alternative Splicing in the Cytochrome P450 Superfamily Expands Protein Diversity to Augment Gene Function and Redirect Human Drug Metabolism.
Drug Metab Dispos
; 45(4): 375-389, 2017 04.
Article
en En
| MEDLINE
| ID: mdl-28188297
ABSTRACT
The human genome encodes 57 cytochrome P450 genes, whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics, and unknown numbers of endogenous compounds, including steroids, retinoids, and eicosanoids. Indeed, P450 genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several National Institutes of Health databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human P450 transcriptome. This review describes a remarkable diversification of the 57 human P450 genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's P450 proteome. Important P450 splice variants from families 1A, 1B, 2C, 2D, 3A, 4F, 19A, and 24A have now been documented, with some displaying alternative subcellular distribution or catalytic function directly linked to a disease pathology. The expansion of P450 transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, trans-splicing between gene transcripts, single-nucleotide polymorphisms, and epigenetic regulation of alternate splicing. Homeostatic regulation of variant P450 expression is influenced also by nuclear receptor signaling, suppression of nonsense-mediated decay or premature termination codons, mitochondrial dysfunction, or host infection. This review focuses on emergent aspects of the adaptive gene-splicing process, which when viewed through the lens of P450-nuclear receptor gene interactions, resembles a primitive immune-like system that can rapidly monitor, respond, and diversify to acclimate to fluctuations in endo-xenobiotic exposure. Insights gained from this review should aid future drug discovery and improve therapeutic management of personalized drug regimens.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Preparaciones Farmacéuticas
/
Empalme Alternativo
/
Sistema Enzimático del Citocromo P-450
/
Epigénesis Genética
Tipo de estudio:
Prognostic_studies
/
Systematic_reviews
Límite:
Humans
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2017
Tipo del documento:
Article