Diversity of common alternative splicing variants of human cytochrome P450 1A1 and their association to carcinogenesis

Abstract

Abstract. Cytochrome P450 1A1 (CYP1A1) belongs to the enzymes of biotransformation of phase I. CYP1A1 performs the catalytic activation of exogenous and endogenous substrates to more carcinogenic metabolites. Overexpression of the wild-type and a recently described splice variant (CYP1A1v, ovarian cancer) are attributed to neoplastic transformation. Here we describe novel CYP1A1 splicing variants commonly and frequently transcribed in leucocytes of healthy volunteers, separated from variants exclusively expressed in tumour cell lines. Interestingly, all the novel splicing variants in leukocytes are generated by employing of two nested splice site pairs, one outer canonical and one inner non-canonical splice site pair, within the exon 2 of the human CYP1A1. In general, the frequent presence of common splicing variants in healthy volunteers has to be consider as a physiological feature of human CYP1A1 transcription process, rather than a signature of carcinogenesis.

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

“…Exon 6 of CYP1A1 appears to be organized for "plug and play" utilization in the brain, where targeted skipping does not compromise the global P450 fold but alters substrate specificity for a spectrum of endogenous substrates, including testosterone. This tissue-specific exon 6 usage of CYP1A1 is complemented by a similar pattern of alternative exon 2 usage found in human endothelial cells, leukocytes, and tumor cells (Leung et al, 2005, Bauer et al, 2007. As shown in Fig.…”

“…As discussed above, a single P450 gene can be translated into multiple, variant protein sequences, solely on the basis of tissue-specific differences in the expression of key gene-splicing machinery [e.g., small nuclear RNA (snRNAs)]. Several alternately spliced CYP1A1 transcripts identified in human brain tissues exemplify this phenomenon, as well as the concept of tissue-specific spliceosome activity (Bauer et al, 2007). Inducible CYP1A1 is constitutively expressed in the brain, where it is localized to neurons in the cortex, cerebellum, and hippocampus.…”

Importance of CYP1A1 and CYP1B1 in bioactivation of benzo[a]pyrene in human lung cell lines

“…The mRNA sequence corresponding to the full-length variant of the protein consists of seven exons. At least two additional splice variants of the protein have been identified in human leukocytes (Bauer et al 2007 1543, 2016; Rifkind, 2006;Shrenk, 1998). CYP1B1 expression is also highly inducible by…”