Alternative splicing events can lead to differential responses to xenobiotics because of the modified synthesis of proteins. In other words, how each new protein variant is able to contribute to metabolism and disease progression is a roll of the dice.
In the Workshop Session “Revising Biology: Alternative Splicing in Toxicology” during the SOT 60th Annual Meeting and ToxExpo, Drs. Annalora, Wright, and Cardoso presented their research on the mechanisms by which alternative splicing alters wild-type protein functions. Among other things, this research may allow for splicing variants to be used as novel biomarkers of exposures and predictors of prognosis.
To highlight how important alternative splicing can be in the process of xenobiotic metabolism, Dr. Annalora offered the example of how splicing variants of P450 enzymes can interfere with the ability of the enzymes to recognize xenobiotics. In his talk, he discussed how both calcifediol (vitamin D3) and the toxicant benzo(a)pyrene are metabolized by P450s, and how alternative splicing can change the fate of the compound. In terms of steroid structure, benzo(a)pyrene looks similar to calcifediol. P450s that are basally expressed to recognize each of these xenobiotics may be alternatively spliced in ways that interfere with the ability of a P450 to recognize the difference between nutrition and pollution.
Alternative splicing is an interesting field of study. In addition to the identification of biomarkers, alternative splicing can help to elucidate the heterogenous responses of individuals to environmental exposures and therapeutic treatments.
The role of alternative splicing has been underappreciated in toxicology because of the detection limits of current RNA and protein analysis methods. However, the panelists in this session were very optimistic. In the words of Dr. Annalora, “In the next decade, we will start to get a much better understanding of the interindividual differences in gene splicing that underlie disease states, and chemical exposures, which will create improved diagnostics and smarter drugs that can address personalized disorders.”
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