The Nematicide Tioxazafen Disrupts Proteasome Function via Cytochrome P450 Bioactivation

Area of Science:

• Biochemistry
• Toxicology
• Nematology

Background:

• Tioxazafen, an effective nematicide, faced commercialization halt due to handler skin reactions.
• Cytochrome P450 enzymes are implicated in xenobiotic metabolism and toxicity.

Purpose of the Study:

• To investigate the bioactivation mechanism of tioxazafen.
• To identify the role of cytochrome P450s in tioxazafen toxicity.
• To elucidate the molecular basis of tioxazafen-induced skin reactions.

Main Methods:

• In vitro bioactivation assays using nematode and human cytochrome P450s.
• Proteasome activity assays in C. elegans.
• Analysis of SKN-1A accumulation and proteasome gene expression.
• Screening of human P450s, including skin-expressed CYP1A1, for tioxazafen toxification.

Main Results:

• Tioxazafen is bioactivated by nematode and human cytochrome P450s into toxic metabolites.
• Bioactivated tioxazafen disrupts proteasome function, leading to SKN-1A accumulation in C. elegans.
• Genetic upregulation of proteasomes confers resistance to tioxazafen lethality.
• Human skin-expressed CYP1A1 toxifies tioxazafen, potentially explaining handler reactions.
• Rabbit CYP1A1 did not bioactivate tioxazafen, indicating species-specific differences.

Conclusions:

• Proteotoxicity is a key mechanism underlying tioxazafen's lethality.
• Human CYP1A1-mediated bioactivation of tioxazafen explains adverse skin reactions.
• Current pre-market toxicological assays may have vulnerabilities in detecting P450-mediated toxification.
• The study provides a framework for prospectively identifying P450 toxication events.