Alternative in vivo models such as Caenorhabditis elegans have been demonstrated to be a useful tool in Pharmacology, especially for the screening of new drugs. In this context, organoselenium compounds have being extensively studied because of their pharmacological properties. This study aimed to evaluate the mechanisms of the stress resistance provided by 4-phenylseleno-7-chloroquinoline in C. elegans against paraquat, a well known prooxidant. The N2 (wild type) worms were exposed to concentrations that ranged of 1 to 1000microM (DL50) and 10microM (nonlethal concentration). To inflict cellular damage, paraquat was used at 500microM.l The treatments were made in liquid medium for 30min, followed by washes to remove the remaining treatment. We have accessed the lethal dose 50% (DL50) and the survival post treatments by counting the alive worms 24h after the treatments. Knockdown strains (daf-16, skn-1, sod-2;3, gcs-1 and trxr-1) were used in the same mode. The compound reverted the mortality induced by paraquat about 20%. This effect was completely lost in the absence of the homologues to the human FOXO and NRF2 transcription factors: DAF-16 and SKN-1. These transcription factors can induce the transcription of protective genes as superoxide dismutase (SOD-2 and SOD-3) and the precursor of glutathione, y-glutamyl cysteine synthetase (GCS-1). In according with this, the same loss of effect was observed in the absence of sod-2,3 and gcs-1. The compound had no effect also in the mutant for thioredoxin reductase 1 (TRXR-1). The observed DL50 were 560microM for N2, whereas the skn-1, sod-2,3 and trxr-1 mutants showed significantly higher sensitivity to the compound (DL50 : 110microM, 35microM and 130microM, respectively). The daf-16 and gcs-1 mutants showed no significantly different toxicity profile (DL50: 620microM and 530microM, respectively. The quinoline ring can generate superoxide radical, what could explain the higher toxicity observed in the sod-2,3 mutant. Quinoline, in mammals, is metabolized by oxy-reductases that can be expressed over induction by NRF2, explaining the role of skn-1 in the compound toxicity. TRXR-1 can reduce disulfide bonds, including organic selenium. Reduced selenium are more toxic that oxidized form, what could explain the role of trxr-1 in the toxicity of the compound, but their pharmacologic role in our study remains as a font of research. The selenoquinoline is capable to revert oxidative damage in a daf-16, skn-1 and trxr-1 dependent way. sod-2,3, skn-1 and trxr-1 also play role in the detoxification of this compound in C. elegans.

Affiliations:
- Universidade Federal do Pampa- UNIPAMPA, Uruguaiana, RS, Brazil
- Universidade Federal de Pelotas, UFPel, Pelotas, RS, Brazil