Abstract

The human genome encodes 57 cytochrome P450 (CYP) genes whose enzyme products metabolize hundreds of drugs, thousands of xenobiotics and unknown numbers of endogenous compounds including steroids, retinoids and icosinoids. Indeed, CYP genes are the first line of defense against daily environmental chemical challenges in a manner that parallels the immune system. Several databases, including PubMed, AceView, and Ensembl, were queried to establish a comprehensive analysis of the full human CYP transcriptome. This review describes a remarkable diversification of the 57 human CYP genes, which may be alternatively processed into nearly 1000 distinct mRNA transcripts to shape an individual's CYP proteome. Important CYP 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 CYP transcript diversity involves tissue-specific splicing factors, transformation-sensitive alternate splicing, trans-splicing between gene transcripts, single-nucleotide polymorphisms (SNPs), and epigenetic regulation of alternate splicing. Homeostatic regulation of variant CYP expression also is influenced by nuclear receptor (NR) signaling, suppression of nonsense mediated decay (NMD) or premature termination codons (PTC), mitochondrial dysfunction or host infection. This review focuses on emergent aspects of the adaptive gene splicing process, which when viewed through the lens of CYP-NR 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.