Chronic Sulfasalazine Treatment in Mice Induces System xc−- Independent Adverse Effects

Frontiers in Pharmacology, 2021 · DOI: 10.3389/fphar.2021.625699 · Published: May 18, 2021

Simple Explanation

This study investigates the side effects of sulfasalazine (SAS) in mice, a drug commonly used to target system xc−. The researchers aimed to determine if these side effects are due to the drug's intended action on system xc− or other unintended effects. The study found that SAS had negative impacts on the survival rate, body weight, and thermoregulation of mice, regardless of whether they had a functional system xc−. This suggests that these adverse effects are independent of the drug's action on this system. The research concludes that the undesirable effects observed with chronic SAS administration are not dependent on its inhibition of system xc−. This highlights the need for developing more selective drugs that target system xc− without causing these off-target effects.

Study Duration

4 weeks

Participants

Six-month-old male xCT−/- and xCT+/+ littermates

Evidence Level

Not specified

Key Findings

1
SAS had a negative impact on the survival rate of mice of both genotypes, independent of its inhibitory action on system xc−.
2
SAS treatment decreased the total distance travelled in the open-ﬁeld test the ﬁrst time the mice encountered the test, but this effect did not persist long-term.
3
SAS influenced body temperature, inducing hypothermia shortly after injection, via xCT-independent mechanisms.

Research Summary

The study investigated the adverse effects of chronic sulfasalazine (SAS) treatment in mice, focusing on whether these effects are related to the inhibition of system xc−. Two different doses of SAS were administered to both system xc−-deficient mice and their wildtype littermates. The results showed that SAS had a negative impact on survival rate, body weight, and thermoregulation in mice of both genotypes, indicating that these effects are independent of system xc−inhibition. The study also observed a transient decrease in the total distance travelled in the open-field test. The research concluded that the observed adverse effects of chronic SAS administration are not dependent on its function as an inhibitor of system xc−. This emphasizes the need for further research to develop safer molecules that selectively target system xc−.

Practical Implications

Drug Development

The findings underscore the importance of developing more selective inhibitors of system xc- to minimize off-target effects and improve the safety profile of potential therapeutics.

Clinical Considerations

Clinicians should be aware of the potential adverse effects of sulfasalazine, such as mortality, weight loss, and thermoregulation issues, which may not be directly related to system xc- inhibition.

Research Focus

Future studies should focus on identifying and characterizing the specific mechanisms underlying the xCT-independent adverse effects of sulfasalazine to better understand its toxicity.

Study Limitations

1
The study was conducted on mice, and the results may not directly translate to humans.
2
The specific mechanisms underlying the xCT-independent adverse effects of SAS were not fully elucidated.
3
The study focused on a limited number of behavioral and histological outcomes, and other potential adverse effects may not have been detected.

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