Caenorhabditis elegans organic cation transporter-2 is a novel drug uptake transporter that mediates induced mutagenesis by environmental genotoxic compounds

Uptake transporters are being studied for roles in the entry of therapeutic drugs into cells and thus can be exploited to improve the treatment of various diseases. The live whole model organism, Caenorhabditis elegans, offers an array of advantages to investigate the roles of these transporters. This organism possesses two organic cation transporters (OCTs), OCT1 and OCT2 that are involved in the uptake of clinically relevant genotoxic anticancer drugs such as doxorubicin and cisplatin into the animal. C. elegans lacking OCT1 displays a shortened lifespan, a decreased brood size, an increased susceptibility to oxidative stress, and certain DNA damaging agents. Remarkably, these phenotypes can be rescued by downregulating the OCT1 paralog, OCT2, leading to the suggestion that OCT1 exerts control on OCT2. Indeed, the loss of OCT1 led to the upregulation of OCT2. OCT2 is an uptake transporter involved in the influx of doxorubicin, as well as a number of other therapeutic agents and chemical compounds, some of which have been identified through ligand-protein docking analyses. The genotoxic compounds entering into C. elegans lead to DNA damage-induced apoptosis of germ cells, a process that can be attenuated by blocking OCT2 function. Thus, by combining the roles of the OCT1 and OCT2 transporters with defects in various DNA repair mechanisms, it is possible to engineer a set of supersensitive C. elegans strains that can serve as the most powerful living sensors to date. These tester C. elegans strains can be used to report on the cytotoxicities and genotoxicities of a battery of old and new drugs developed by pharmaceuticals, undocumented toxicants generated by various industries, and compounds that can cause cancers and are present in trace amounts in the environment around the world. These efforts are attainable as C. elegans can live in the soil and water, and a multitude of tools are available to monitor several readouts from the animals.